Fused imidazolyl derivatives, their preparation and use as medicaments

ABSTRACT

The present invention relates to new fused imidazolyl derivatives having a high affinity for sigma receptors, especially sigma-1 receptors, as well as to the process for the preparation thereof, to compositions comprising them, and to their use as medicaments.

FIELD OF THE INVENTION

The present invention relates to new fused imidazolyl derivatives havinga high affinity for sigma receptors, especially sigma-1 receptors, aswell as to the process for the preparation thereof, to compositionscomprising them, and to their use as medicaments.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been improved in recent yearsby better understanding of the structure of proteins and otherbiomolecules associated with target diseases. One important class ofthese proteins are the sigma (σ) receptors, cell surface receptors ofthe central nervous system (CNS) which may be related to the dysphoric,hallucinogenic and cardiac stimulant effects of opioids. From studies ofthe biology and function of sigma receptors, evidence has been presentedthat sigma receptor ligands may be useful in the treatment of psychosisand movement disorders such as dystonia and tardive dyskinesia, andmotor disturbances associated with Huntington's chorea or Tourette'ssyndrome and in Parkinson's disease (Walker, J. M. et al,Pharmacological Reviews, 1990, 42, 355). It has been reported that theknown sigma receptor ligand rimcazole clinically shows effects in thetreatment of psychosis (Snyder, S. H., Largent, B. L. J. Neuropsychiatry1989, 1, 7). The sigma binding sites have preferential affinity for thedextrorotatory isomers of certain opiate benzomorphans, such as(+)-SKF-10047, (+)-cyclazocine, and (+)-pentazocine and also for somenarcoleptics such as haloperidol.

“The sigma receptor/s” as used in this application is/are well known anddefined using the following citation: This binding site represents atypical protein different from opioid, NMDA, dopaminergic, and otherknown neurotransmitter or hormone receptor families (G. Ronsisvalle etal. Pure Appl. Chem. 73, 1499-1509 (2001)).

The sigma receptor has at least two subtypes, which may be discriminatedby different drugs. (+)-SKF-10047 has nanomolar affinity for the sigma 1(σ₁) site, and micromolar affinity for the sigma 2 (σ₂) site.Haloperidol has similar affinities for both subtypes.

The σ₁ receptor is a chaperone protein expressed in numerous adultmammal tissues (e.g. central nervous system, ovary, testicle, placenta,adrenal gland, spleen, liver, kidney, gastrointestinal tract) as well asin embryo development from its earliest stages, and is apparentlyinvolved in a large number of physiological functions. Its high affinityfor various pharmaceuticals has been described, such as for(+)-SKF-10047, (+)-pentazocine, haloperidol and rimcazole, among others,known ligands with analgesic, anxiolytic, antidepressive, antiamnesic,antipsychotic and neuroprotective activity. The σ₁ receptor is of greatinterest in pharmacology in view of its possible physiological role inprocesses related to analgesia, anxiety, addiction, amnesia, depression,schizophrenia, stress, neuroprotection and psychosis [Kaiser et al(1991) Neurotransmissions 7 (1): 1-5], [Walker, J. M. et al,Pharmacological Reviews, 1990, 42, 355] and [Bowen W. D. (2000)Pharmaceutica Acta Helvetiae 74: 211-218].

The σ₂ receptor is also expressed in numerous adult mammal tissues (e.g.nervous system, immune system, endocrine system, liver, kidney). σ₂receptors can be components in a new apoptosis route that may play animportant role in regulating cell proliferation or in cell development.This route seems to consist of σ₂ receptors joined to intracellularmembranes, located in organelles storing calcium, such as theendoplasmic reticulum and mitochondria, which also have the ability torelease calcium from these organelles. The calcium signals can be usedin the signaling route for normal cells and/or in induction ofapoptosis.

Agonists of σ₂ receptors induce changes in cell morphology, apoptosis inseveral types of cell lines and regulate the expression ofp-glycoprotein mRNA, so that they are potentially useful asantineoplasic agents for treatment of cancer. In fact, σ₂ receptoragonists have been observed to induce apoptosis in mammary tumour celllines resistant to common antineoplasic agents that damage DNA. Inaddition, agonists of σ₂ receptors enhance the cytotoxic effects ofthese antineoplasic agents at concentrations in which the agonist is notcytotoxic. Thus, agonists of σ₂ receptors can be used as antineoplasicagents at doses inducing apoptosis or at sub-toxic doses in combinationwith other antineoplasic agents to revert the resistance to the drug,thereby allowing using lower doses of the antineoplasic agent andconsiderably reducing its adverse effects.

Antagonists of σ₂ receptors can prevent the irreversible motor sideeffects caused by typical neuroleptic agents. In fact, it has been foundthat antagonists of σ₂ receptors can be useful as agents for improvingthe weakening effects of delayed dyskinesia appearing in patients due tochronic treatment of psychosis with typical antipsychotic drugs, such ashaloperidol. σ₂ receptors also seem to play a role in certaindegenerative disorders in which blocking these receptors could beuseful.

Endogenous sigma ligands are not known, although progesterone has beensuggested to be one of them. Possible sigma-site-mediated drug effectsinclude modulation of glutamate receptor function, neurotransmitterresponse, neuroprotection, behavior, and cognition (Quirion, R. et al.Trends Pharmacol. Sci., 1992, 13:85-86). Most studies have implied thatsigma binding sites (receptors) are plasmalemmal elements of the signaltransduction cascade. Drugs reported to be selective sigma ligands havebeen evaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad.Sci., 1996, 93:8072-8077). The existence of σ receptors in the CNS,immune and endocrine systems have suggested a likelihood that it mayserve as link between the three systems.

In view of the potential therapeutic applications of agonists orantagonists of the a receptor, a great effort has been directed to findselective ligands. Different a receptor ligands have been reported.

For instance, the international patent application WO-2008/055932 dealswith 1,2,4-triazole compounds having good activity towards a receptors.WO-2009/071657 also reports tricyclic triazolic compounds having goodactivity towards a receptors. Pyrazoles compounds have been described inthe international application WO-2011/147910 as σreceptor inhibitors.

Some fused compounds have also been reported as a ligands. For instancethe pyrazolo[3,4-d]pyrimidine disclosed in the international applicationWO-2013/010950, as well as the pyrazolo[1,5-a]pyridines described inWO-2013/124341.

Nevertheless, there is still a need to find compounds havingpharmacological activity towards the σreceptor, being both effective andselective, and having good “drugability” properties, i.e. goodpharmaceutical properties related to administration, distribution,metabolism and excretion.

SUMMARY OF THE INVENTION

The present invention discloses novel compounds with high affinity tosigma receptors which might be used for the treatment of sigma relateddisorders or diseases.

In a main aspect, the present invention is directed to novel fusedimidazolyl derivatives of general formula (I):

where R₁, R₂ and n are as defined below.

Another object of the invention relates to the different processes forpreparation of compounds of general formula (I).

Another object of the invention refers to the use of such compounds ofgeneral formula (I) for the treatment or prophylaxis of σreceptormediated diseases or conditions, especially σ₁ mediated diseases orconditions. Within the group of diseases or conditions mediated by the areceptor for which the compounds of the invention are effective,diarrhea, lipoprotein disorders, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, obesity, migraine, pain, arthritis, hypertension,arrhythmia, ulcer, glaucoma, learning, memory and attention deficits,cognition disorders, neurodegenerative diseases, demyelinating diseases,addiction to drugs and chemical substances including cocaine,amphetamine, ethanol and nicotine; tardive diskinesia, ischemic stroke,epilepsy, stroke, stress, cancer, psychotic conditions, in particulardepression, anxiety or schizophrenia; inflammation or autoimmunediseases, may be cited. Compounds of the invention are very good and areespecially effective for the treatment and prophylaxis of pain,especially neuropathic pain, inflammatory pain or other pain conditionsinvolving allodynia and/or hyperalgesia.

It is also an object of the invention to provide pharmaceuticalcompositions comprising one or more compounds of general formula (I)with at least one pharmaceutically acceptable excipient. Thepharmaceutical compositions in accordance with the invention can beadapted in order to be administered by any route of administration, beit orally or parenterally, such as pulmonarily, nasally, rectally and/orintravenously. Therefore, the formulation in accordance with theinvention may be adapted for topical or systemic application,particularly for dermal, subcutaneous, intramuscular, intra-articular,intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous,vaginal, oral or parenteral application.

DETAILED DESCRIPTION OF THE INVENTION

The invention first relates to a compound of general formula (I):

where

R₁ is selected from the group consisting of —NR₄COR₃, —NHCONHR₃,—(C(R₅₁R₅₂))_(m)—R₆, and —NR₇₁R₇₂;

R₂ is selected from the group consisting of —(C(R₈₁R₈₂))_(p)—R₉, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted heterocycloalkyl group;

R₃ is selected from the group consisting of a linear or branched,substituted or unsubstituted C₁₋₁₀ aliphatic radical, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkylalkyl group, a substituted or unsubstituted heterocycloalkylgroup, a substituted or unsubstituted heterocycloalkylalkyl group;

R₄, is selected from the group consisting of a hydrogen atom, a linearor branched, substituted or unsubstituted C₁₋₁₀ aliphatic radical, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted arylalkyl group, a substituted orunsubstituted heterocycloalkyl group, a substituted or unsubstitutedheterocycloalkylalkyl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heteroarylalkyl group;

R₅₁, R₅₂, R₈₁ and R₈₂ are selected independently from the groupconsisting of a hydrogen atom, a linear or branched, substituted orunsubstituted C₁₋₃ aliphatic radical;

R₆ is selected from the group consisting of a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup;

R₇₁ is selected from the group consisting of a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkylalkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted arylalkyl group, a substituted orunsubstituted heterocycloalkyl group, a substituted or unsubstitutedheterocycloalkylalkyl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heteroarylalkyl group;

R₇₂ is selected from the group consisting of a hydrogen atom, a linearor branched, substituted or unsubstituted C₁₋₃ aliphatic radical;

R₉ is selected from the group consisting of a substituted orunsubstituted cycloalkyl group, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heterocycloalkyl group, asubstituted or unsubstituted heteroaryl group;

n is 1, 2, or 3;

m is 1, 2, or 3;

p is 1, 2, or 3;

as well as one of the stereoisomers, preferably enantiomers ordiastereomers, a racemate or as a mixture of at least two of thestereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a pharmaceutically acceptable salt or solvate thereof.

“Halogen” or “halo” as referred in the present invention representfluorine, chlorine, bromine or iodine.

Aliphatic radical C₁₋₁₀, as referred to in the present invention, areoptionally mono- or polysubstituted and may be branched or unbranched,saturated or unsaturated. Unsaturated aliphatic radicals, as defined inthe present invention, include alkenyl and alkynyl radicals. Preferredaliphatic radicals according to the present invention include but arenot restricted to methyl, ethyl, vinyl (ethenyl), ethynyl, propyl,n-propyl, isopropyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl,n-butyl, iso-butyl, sec-butyl, tert-butyl butenyl, butynyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, n-pentyl,isopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,hexyl, 1-methylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Aliphaticradicals as defined in the present invention are optionally mono- orpolysubstituted by one or more substituents independently selected froma C₁₋₆ alkyl group, a linear or branched C₁₋₆ alkoxy group, —F, —Cl, —I,—Br, —CF₃, —CH₂F, —CHF₂, —CN, —OH, —SH, —NH₂, oxo, —(C═O)R′, —SR′,—SOR′, —Sσ₂R′, —NHR′, —NR′R″ whereby R′ and optionally R″ for eachsubstitutent independently represents a linear or branched C₁₋₆-alkylradical.

Preferred aliphatic radicals C₁₋₁₀ according to the invention are alkylradicals C₁₋₁₀.

Alkyl radicals C₁₋₁₀, as referred to in the present invention, aresaturated aliphatic radicals C₁₋₁₀. They may be linear or branched andsubstituted or unsubstituted. Among the alkyl radicals C₁₋₁₀, the alkylradicals C₁₋₆ are preferred. The C₁₋₆ alkyl radicals as expressed in thepresent invention means an alkyl radical of 1, 2, 3, 4, 5 or 6 carbonatoms. In a more preferred aspect of the invention, the alkyl radicalsare unsubstituted.

Cycloalkyl group C₃₋₉, as referred to in the present invention, areunderstood as meaning saturated and unsaturated (but not aromatic),cyclic hydrocarbons, which can optionally be unsubstituted, mono- orpolysubstituted. In particular the cycloalkyl groups according to theinvention are saturated C₃₋₉ cycloalkyl group. In these radicals, forexample C₃₋₄-cycloalkyl represents C₃- or C₄-cycloalkyl, C₃₋₆-cycloalkylrepresents C₃-, C₄- or C₅-cycloalkyl, etc. Cycloalkyl group also includemono- or polyunsaturated, preferably monounsaturated, but not aromaticcycloalkyl groups. Examples for cycloalkyl group preferably include butare not restricted to cyclopropyl, 2-methylcyclopropyl,cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl,cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, noradamantyl, tetralinylor indanyl. Cycloalkyl group C₃₋₉, as defined in the present invention,are optionally mono- or polysubstituted by one or more substitutentsindependently selected from a C₁₋₆ alkyl group, a linear or branchedC₁₋₆ alkoxy group, —F, —Cl, —I, —Br, —CF₃, —CH₂F, —CHF₂, —CN, —OH, —SH,—NH₂, oxo, —(C═O)R′, —SR′, —SOR′, —Sσ₂R′, —NHR′, —NR′R″ whereby R′ andoptionally R″ for each substitutent independently represents a linear orbranched C₁₋₆-alkyl radical. In a more preferred aspect of theinvention, the cycloalkyl group C₃₋₉ represents a group chosen fromcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl,cyclopentylmethyl and cyclohexyl, and especially a cyclohexyl group.

A heterocycloalkyl group, as referred to in the present invention, isunderstood as meaning saturated and unsaturated (but not aromatic),cyclic hydrocarbons in which optionally at least one carbon atom isreplaced by a heteroatom, preferably S, N or O. Heterocycloalkyl groupalso include mono- or polyunsaturated, preferably monounsaturated, butnot aromatic heterocycloalkyl groups. Heterocycloalkyl group accordingto the invention can optionally be unsubstituted, mono- orpolysubstituted by one or more substitutents independently selected froma C₁₋₆ alkyl radical, a linear or branched C₁₋₆ alkoxy group, —F, —Cl,—I, —Br, —CF₃, —CH₂F, —CHF₂, —CN, —OH, —SH, —NH₂, oxo, —(C═O)R′, —SR′,—SOR′, —Sσ₂R′, —NHR′, —NR′R″ whereby R′ and optionally R″ for eachsubstitutent independently represents a linear or branched C₁₋₆-alkylradical. Examples for heterocycloalkyl group preferably include but arenot restricted to pyrrole, pyrroline, pyrrolidine, pyrrolidineone,pyrazoline, pyrazolinone, oxopyrazolinone, aziridine, azetidine,tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyrane,tetrahydrofurane, tetrahydro-2H-thiopyran, dioxane, dioxolane,oxathiolane, oxazolidine, thiirane, thietane, thiolane, thiane,thiazolidine, pyrazine piperidine, piperazine, morpholine, azepane ordiazepane. Advantageously, the heterocycloalkyl group of the compoundsaccording to the invention represents a group chosen from pyrrole,pyrroline, pyrrolidine, pyrazoline, tetrahydropyrrole, tetrahydropyrane,tetrahydrofurane, dioxane, pyrazine piperidine, piperazine andmorpholine and especially a morpholine group.

An aryl group, as referred to in the present invention, is understood asmeaning aromatic ring systems without heteroatoms even in only one ofthe rings. These aryl groups may optionally be mono- or polysubstitutedby one or more substitutents independently selected from a C₁₋₆ alkylradical, a linear or branched C₁₋₆ alkoxy group, —F, —Cl, —I, —Br, —CF₃,—CH₂F, —CHF₂, —CN, —OH, —SH, —NH₂, oxo, —(C═O)R′, —SR′, —SOR′, —Sσ₂R′,—NHR′, —NR′R″ whereby R′ and optionally R″ for each substitutentindependently represents a linear or branched C₁₋₆-alkyl radical.Preferred examples of aryl radicals include but are not restricted tophenyl, naphthyl, fluoranthenyl, fluorenyl, or anthracenyl radicals,which may optionally be mono- or polysubstituted, if not definedotherwise. In a more preferred aspect of the invention, the aryl groupis a phenyl group.

A heteroaryl group, is understood as meaning aromatic ring system inwhich at least one carbon atom is replaced by a heteroatom chosen fromthe group consisting of nitrogen, oxygen and/or sulfur and mayoptionally be mono- or polysubstituted by one or more substitutentsindependently selected from a C₁₋₆ alkyl radical, a linear or branchedC₁₋₆ alkoxy group, F, Cl, I, Br, CF₃, CH₂F, CHF₂, CN, OH, SH, NH₂, oxo,(C═O)R′, SR′, SOR′, SO₂R′, NHR′, NR′R″ whereby R′ and optionally R″ foreach substitutent independently represents a linear or branched C₁₋₆alkyl radical. Preferred examples of heteroaryls include but are notrestricted to furan, benzofuran, thiophene, benzothiophene, pyridine,pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine,benzo-1,2,5-thiadiazole, benzothiazole, triazole, pyrazole, isoxazole,indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole,carbazole and quinazoline. In a more preferred aspect of the invention,the heteroaryl group is a pyridyl group.

In a particularly preferred embodiment of the present invention, thealkyl radicals C₁₋₁₀, the cycloalklyl group C₃₋₉, the heterocycloalkylgroup, the aryl group and the heteroaryl group are unsubstituted orsubstituted by one or more substituents selected from a C₁₋₆ alkylradical, a linear or branched C₁₋₆ alkoxy group, F, Cl, I, Br and OH.

The terms “condensed” or “fused” according to the present invention meanthat a ring or ring-system is attached to at least another ring orring-system, whereby the rings or ring systems have at least one bond incommon, and whereby the terms “annulated” or “annelated” are also usedby those skilled in the art to designate this kind of attachment.

The term “ring system” according to the present invention refers to ringsystems comprising saturated, unsaturated or aromatic carbocyclic ringsystems which contain optionally at least one heteroatom as ring memberand which are optionally at least mono-substituted. Said ring systemsmay be condensed to other carbocyclic ring systems such as aryl groups,naphtyl groups, heteroaryl groups, cycloalkyl groups, etc.

The term “salt” is to be understood as meaning any form of the activecompound according to the invention in which this assumes an ionic formor is charged and is coupled with a counter-ion (a cation or anion) oris in solution. By this are also to be understood complexes of theactive compound with other molecules and ions, in particular complexeswhich are complexed via ionic interactions.

The term “physiologically acceptable salt” or “pharmaceuticallyacceptable salt” is understood in particular, in the context of thisinvention, as salt (as defined above) formed either with aphysiologically tolerated acid, that is to say salts of the particularactive compound with inorganic or organic acids which arephysiologically tolerated-especially if used on humans and/or mammals—orwith at least one, preferably inorganic, cation which arephysiologically tolerated—especially if used on humans and/or mammals.Examples of physiologically tolerated salts of particular acids aresalts of: hydrochloric acid, hydrobromic acid, sulfuric acid,hydrobromide, monohydrobromide, monohydrochloride or hydrochloride,methiodide, methanesulfonic acid, formic acid, acetic acid, oxalic acid,succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid,lactic acid, citric acid, glutamic acid, hippuric acid picric acidand/or aspartic acid. Examples of physiologically tolerated salts ofparticular bases are salts of alkali metals and alkaline earth metalsand with NH₄.

The term “solvate” is to be understood as meaning any form of the activecompound according to the invention in which this compound has attachedto it via non-covalent binding another molecule (most likely a polarsolvent) especially including hydrates and alcoholates, e.g.methanolate.

An aspect of the invention relates to prodrugs of compounds of formula(I) as defined above.

The term “prodrug” is used in its broadest sense and encompasses thosederivatives that are converted in vivo to the compounds of theinvention. Such derivatives would readily occur to those skilled in theart, and include, depending on the functional groups present in themolecule and without limitation, the following derivatives of thecompounds of the invention: esters, amino acid esters, phosphate esters,metal salts sulfonate esters, carbamates, and amides. Examples of wellknown methods of producing a prodrug of a given acting compound areknown to those skilled in the art and can be found e.g. inKrogsgaard-Larsen et al. “Textbook of Drug design and Discovery” Taylor& Francis (april 2002).

Any compound that is a prodrug of a compound of formula (I) is withinthe scope of the invention. Particularly favored prodrugs are those thatincrease the bioavailability of the compounds of this invention whensuch compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

In a particular embodiment of the compounds of formula (I) according tothe invention R₁ represents a group —NR₇₁R₇₂.

In particularly preferred embodiment of the compounds of formula (I)according to the invention, R₁ represents a group —NR₇₁R₇₂ in which R₇₁is a substituted or unsubstituted aryl group and R₇₂ is a hydrogen atom.

In another embodiment, the compounds of formula (I) of the presentinvention are those where R₁ represents a group —(C(R₅₁R₅₂))_(m)—R₆ inwhich R₆ is preferably a substituted or unsubstituted aryl group.

In a further particular embodiment of the compounds of formula (I)according to the invention, R₁ is selected from the group consisting of—NR₄COR₃, and —NHCONHR₃.

A further aspect of the present invention is directed particularly tocompounds of formula (I) according to the invention where R₂ is a—(C(R₈₁R₈₂))_(p)—R₉ group.

A further aspect of the invention is directed to compounds of formula(I) according to the invention where R₂ is a —(C(R₈₁R₈₂))_(p)—R₃ groupin which R₅₁ and R₅₂ represent each a hydrogen atom. In a still furtherparticular aspect of the compounds of formula (I) according to theinvention the group R₉ represents a substituted or unsubstitutedcycloalkyl group. In another further particular aspect of the compoundsof formula (I) according to the invention the group R₉ represents asubstituted or unsubstituted aryl group. In another further particularaspect of the compounds of formula (I) according to the invention thegroup R₉ represents a substituted or unsubstituted heterocycloalkylgroup. In another further particular aspect of the compounds of formula(I) according to the invention the group R₉ represents a substituted orunsubstituted heteroaryl group.

A still further aspect of the invention is directed to compounds offormula (I) according to the invention where, taking together orseparately n is 1 or 2, preferably 1, m is 1, p is 1.

In a more preferred variant of the invention, the sigma ligand offormula (I) is selected from:

-   -   1-(8-(cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-yl)-3-ethylurea,    -   1-(7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-ethylurea,    -   1-(7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-propylurea,    -   1-tert-butyl-3-(7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)urea,    -   7-(cyclohexylmethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-(cyclohexylmethyl)-N-(3,5-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-(cyclohexylmethyl)-N-(3-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-(cyclohexylmethyl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-benzyl-N-(3-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-benzyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-(3,5-difluorophenyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-phenyl-7-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-benzyl-N-(2-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-(4-((3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl)phenyl)acetamide,    -   N-(3-methoxyphenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,    -   N-(4-fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,    -   N-(3-chloro-2-fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,    -   N-(3,5-difluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,    -   3-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-ylamino)phenol,    -   7-(4-fluorobenzyl)-N-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-benzyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-(2-bromo-6-chlorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,    -   N-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N-phenylpropionamide,    -   N-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N-(3-hydroxyphenyl)propionamide,    -   N-(3-hydroxyphenyl)-N-(7-phenethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propionamide,    -   7-benzyl-N-methyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-benzyl-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   3-benzyl-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine        trifluoroacetate,    -   3-(4-fluorobenzyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine        hydrochloride,    -   7-(cyclohexylmethyl)-3-(4-fluorobenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine        hydrochloride,    -   7-phenethyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-phenyl-7-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-phenyl-7-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   3-(7-phenethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-ylamino)phenol,    -   7-(2,4-difluorobenzyl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-((4,4-difluorocyclohexyl)methyl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-(4-fluorophenyl)-7-((5-fluoropyridin-2-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-(4-fluorophenyl)-7-((6-fluoropyridin-3-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   N-(4-fluorophenyl)-7-((6-methoxypyridin-3-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-cyclohexyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-(3-methoxyphenethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-(4-methoxyphenethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-(3-(3-methoxyphenyl)propyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   7-(3-(4-methoxyphenyl)propyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,    -   3-(2-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethyl)phenol,    -   4-(2-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethyl)phenol,    -   3-(3-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)propyl)phenol,    -   4-(3-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)propyl)phenol,

or a pharmaceutically acceptable salt or solvate thereof.

Any compound referred to herein is intended to represent such specificcompound as well as certain variations or forms. In particular,compounds referred to herein may have asymmetric centers and thereforeexist in different enantiomeric or diastereomeric forms. Thus, any givencompound referred to herein is intended to represent any one of aracemate, one or more enantiomeric forms, one or more diastereomericforms, and mixtures thereof. Likewise, stereoisomerism or geometricisomerism about the double bond is also possible, therefore in somecases the molecule could exist as (E)-isomer or (Z)-isomer (trans andcis isomers). If the molecule contains several double bonds, each doublebond will have its own stereoisomerism, that could be the same as, ordifferent to, the stereoisomerism of the other double bonds of themolecule. Furthermore, compounds referred to herein may exist asatropisomers. All the stereoisomers including enantiomers,diastereoisomers, geometric isomers and atropisomers of the compoundsreferred to herein, and mixtures thereof, are considered within thescope of the present invention.

Furthermore, any compound referred to herein may exist as tautomers.Specifically, the term tautomer refers to one of two or more structuralisomers of a compound that exist in equilibrium and are readilyconverted from one isomeric form to another. Common tautomeric pairs areamine-imine, amide-imidic acid, keto-enol, lactam-lactim, etc.

Unless otherwise stated, the compounds of the invention are also meantto include isotopically-labelled forms i.e. compounds which differ onlyin the presence of one or more isotopically-enriched atoms. For example,compounds having the present structures except for the replacement of atleast one hydrogen atom by a deuterium or tritium, or the replacement ofat least one carbon by ¹³C- or ¹⁴C-enriched carbon, or the replacementof at least one nitrogen by ¹⁵N-enriched nitrogen are within the scopeof this invention.

The compounds of formula (I) or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels. Purity levels for thedrug substance are preferably above 50%, more preferably above 70%, mostpreferably above 90%. In a preferred embodiment it is above 95% of thecompound of formula (I), or of its salts, solvates or prodrugs.

In another aspect, the invention refers to the processes for obtainingthe compounds of general formula (I).

Compounds of formula (I) as defined above are prepared starting fromcompounds of formula (II):

-   -   wherein n and R₉ have the same meaning than above,        which react with an azidating agent, for example        p-C₁₂(C₆H₄)SO₂N₃, in the presence of an organic base, such as        for example nBuLi, in an inert organic solvent, in particular as        THF, at low temperatures, preferably at about −78° C., to give        compounds of formula (III):

-   -   wherein n and R₉ are as defined above,        which are submitted to a reduction by hydrogenation under a        hydrogen atmosphere with a suitable catalyst, preferably        palladium in an organic solvent such as ethanol, methanol, ethyl        acetate or a mixture of two of them, or alternatively, in the        presence of a suitable reducing agent as a metallic hydride,        preferably lithium aluminium hydride in an organic solvent, such        as diethyl ether, to give compounds of formula (IV):

-   -   wherein n and R₉ are as defined above,        which may be reacted with an isocyanate of formula R₃—N═C═O, R₃        being as defined above for formula (I), to give bisureas of        formula (V):

-   -   wherein n, R₃ and R₉ are as defined above,        which are reacted with a base, such as K₂CO₃, in the presence of        an organic solvent, preferably a polar solvent such as MeOH, to        yield compounds of formula (Ia):

-   -   a particular case of compounds of formula (I) according to the        present invention in which R₁ represents a —NHCONHR₃ group and        n, R₃ and R₉ are as defined for formula (I) above,        or,        compounds of formula (IV) as defined above which are acylated by        a compound of formula R₃COX where X is an halogen atom and R₃ is        as defined above for formula (I), preferably in an aprotic        solvent such as dichloromethane, toluene or tetrahydrofuran in        the presence of an organic base such as        N,N-diisopropylethylamine or pyridine, to yield compounds of        formula (Ib):

-   -   a particular case of compounds of formula (I) according to the        present invention in which R₁ represents a —NR₄COR₃ group, R₄        represents a hydrogen atom, and n, R₃ and R₉ are as defined for        formula (I) above, or,        compounds of formula (IV) as defined above which are reacted        with a compound of formula R₇₁X where X is an halogen atom, and        R₇₁ is selected from the group consisting of a substituted or        unsubstituted aryl group and substituted or unsubstituted        heteroaryl group, in an aprotic inert organic solvent such as        toluene or dioxane, in the presence of a palladium catalyst such        as Pd₂(dba)₃, and an organophosphorous ligand such as Xantphos        or BrettPhos and a base such as KOtBu or NaOtBu, to yield        compounds of formula (Ic):

-   -   a particular case of compounds of formula (I) according to the        present invention in which R₁ represents a —NR₇₁R₇₂ group, R₇₁        is selected from the group consisting of a substituted or        unsubstituted aryl group and substituted or unsubstituted        heteroaryl group, R₇₂ represents a hydrogen atom, and n and R₉        are as defined above for formula (I),        compounds of formula (Ic) which may be submitted to an acylation        reaction with a compound of formula R₃COX where X is an halogen        atom and R₃ is as defined above for formula (I), preferably in        an aprotic solvent such as dichloromethane, toluene or        tetrahydrofuran in the presence of an organic base such as        N,N-diisopropylethylamine or pyridine, to yield compounds of        formula (Id):

-   -   a particular case of compounds of formula (I) according to the        present invention in which R₁ represents a —NR₄COR₃ group, n, R₃        and R₉ are as defined above for formula (I), and R₄ is selected        from the group consisting of a substituted or unsubstituted aryl        group and substituted or unsubstituted heteroaryl group,        compounds of formula (Ic) which may be reacted with a compound        of formula R₇₂X where X is an halogen atom, and R₇₂ is a linear        or branched, substituted or unsubstituted C₁₋₃ aliphatic        radical, in an aprotic polar organic solvent such as        dimethylformamide in the presence of a base such as sodium        hydride to yield compounds of formula (Ie):

-   -   a particular case of compounds of formula (I) according to the        present invention in which R₁ represents a —NR₇₁R₇₂ group, R₇₁        is selected from the group consisting of a substituted or        unsubstituted aryl group and substituted or unsubstituted        heteroaryl group, R₇₂ represents a linear or branched,        substituted or unsubstituted C₁₋₃ aliphatic radical, and n and        R₉ are as defined above for formula (I),        compounds of formula (Ic), which, in the case where R₉        represents a phenyl group, may be debenzylated following known        methods in the art, such as hydrogenation under palladium        catalysis in the presence of an organic solvent such as ethyl        alcohol to give compounds of formula (VI):

-   -   wherein R₇₁ is selected from the group consisting of a        substituted or unsubstituted aryl group and substituted or        unsubstituted heteroaryl group, and n is as defined above,        which are then submitted to a reductive amination process by        reaction with aldehydes or ketones of formula R₂═O, where R₂ is        as defined above, in the presence of a reducing agent such as        NaBH(OAc)₃ in an inert organic solvent such as THF or        acetonitrile, to yield compounds of formula (If):

-   -   a particular case of compounds of formula (I) according to the        present invention in which R₁ represents a —NR₇₁R₇₂ group, R₇₁        is selected from the group consisting of a substituted or        unsubstituted aryl group and substituted or unsubstituted        heteroaryl group, R₇₂ represents a hydrogen atom, and, n and R₂        are as defined above for formula (I).

Compounds of formula (I) as defined above may also be prepared startingfrom compounds of formula (IV) as defined above which are then submittedto a reductive amination process by reaction with aldehydes or ketonesof formula R₇₁═O where R₇₁ represents a linear or branched, substitutedor unsubstituted C₁₋₁₀ aliphatic radical, a substituted or unsubstitutedcycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group,a substituted or unsubstituted arylalkyl group, a substituted orunsubstituted heterocycloalkyl group, a substituted or unsubstitutedheterocycloalkylalkyl group, or a unsubstituted heteroarylalkyl group,in the presence of a reducing agent such as NaBH(OAc)₃ in an inertorganic solvent such as THF or acetonitrile, to yield compounds offormula (Ig):

-   -   a particular case of compounds of formula (I) according to the        present invention in which R₁ represents a —NR₇₁R₇₂ group, R₇₁        is selected from the group consisting of a linear or branched,        substituted or unsubstituted C₁₋₁₀ aliphatic radical, a        substituted or unsubstituted cycloalkyl group, a substituted or        unsubstituted cycloalkylalkyl group, a substituted or        unsubstituted arylalkyl group, a substituted or unsubstituted        heterocycloalkyl group, a substituted or unsubstituted        heterocycloalkylalkyl group, or a unsubstituted heteroarylalkyl        group, R₇₂ represents a hydrogen atom, and n and R₉ are as        defined above for formula (I).

Compounds of formula (I) as defined above may alternatively be preparedstarting from compounds of formula (II) as defined above which reactwith a compound of formula R₆—(C(R₅₁R₅₂))_((m′))—CHO where R₆, R₅₁, R₅₂are as defined above and m′ is 0, 1 or 2, to give compounds of formula(VII):

-   -   wherein R₅₁, R₅₂, R₆, R₉, m′ and n are as defined above, which        are reduced in the presence of an organosilane, such as        triethylsilane, and an acid, such as trifluoroacetic acid, to        yield compounds of formula (Ih):

-   -   a particular case of compounds of formula (I) of the present        invention in which R₁ represents R₆—(C(R₅₁R₅₂))m′-CH₂—, and R₅₁,        R₅₂, R₆, R₉, m′ and n are as defined above.

In the process described above, aldehydes or ketones of formula R₂═O orR₇₁═O mean that the carbonyl group is formed on any carbon atom of thegroups defined for R₂ and R₇₁ respectively in formula (I) above.

Compounds of formula (II) are prepared by known methods, and inparticular starting from compounds of formula (VIII):

which are reacted with a compound of formula HO—CH₂—(CH₂)_(n)—NH—CH₂—R₉where R₉ and n are as defined for formula (I) above, in the presence ofa reducing agent, such as NaBH(OAc)₃ in an inert organic solvent, suchas THF or acetonitrile, to give compounds of formula (IXa):

-   -   where R₉ and n are as defined above,        or alternatively, which react with a compound of formula        HO—CH₂—(CH₂)n-NH₂ in the same condition, to give compounds of        formula (IXb):

-   -   where n is as defined above,        which are then submitted to a second reductive amination in the        presence of R₉—CHO in which R₉ is as defined above, to give a        compound of formula (IXa) as defined above,        compounds of formula (IXa) which react with thionyl chloride to        give the corresponding compounds (Xa):

which are submitted to a cyclisation reaction in the presence of anorganic base such as triethylamine in an organic solvent such asacetonitrile, in a range of temperature from about 25° C. to reflux, toyield compounds of formula (II) as defined above:

-   -   where n is as defined above.

Starting compounds of the above mentioned processes of synthesis areeither commercially available, or easily prepared by known methods tothe skilled artisan.

An additional aspect of the invention relates to the therapeutic use ofthe compounds of general formula (I). As mentioned above, compounds ofgeneral formula (I) show a strong affinity to σ receptors and can behaveas agonists, antagonists, inverse agonists, partial antagonists orpartial agonists thereof. Preferably they behave as antagonists, inparticular antagonists of the σ₁ receptor. Therefore, compounds ofgeneral formula (I) are useful as medicaments.

They are suitable for the treatment and the prophylaxis of disorders anddiseases mediated by σ receptors, especially, σ₁ receptors. In thissense, compounds of formula (I) are very good anxiolitic andimmunosuppressant and are very useful in the treatment and prophylaxisof diarrhoea, lipoprotein disorders, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, obesity, migraine, pain,arthritis, hypertension, arrhythmia, ulcer, glaucoma, learning, memoryand attention deficits, cognition disorders, neurodegenerative diseases,demyelinating diseases, addiction to drugs and chemical substancesincluding cocaine, amphetamine, ethanol and nicotine; tardivediskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychoticconditions, in particular depression, anxiety or schizophrenia;inflammation or autoimmune diseases.

The compounds of formula (I) are especially suited for the treatment ofpain, especially neuropathic pain, inflammatory pain or other painconditions involving allodynia and/or hyperalgesia. PAIN is defined bythe International Association for the Study of Pain (IASP) as “anunpleasant sensory and emotional experience associated with actual orpotential tissue damage, or described in terms of such damage (IASP,Classification of chronic pain, 2nd Edition, IASP Press (2002), 210).Even though pain is always subjective its causes or syndromes can beclassified.

In a preferred embodiment the pain is selected from medium to severepain, visceral pain, chronic pain, cancer pain, migraine, inflammatorypain, acute pain or neuropathic pain, allodynia or hyperalgesia, alsopreferably including mechanical allodynia or thermal hyperalgesia.

In another preferred embodiment compounds of the invention are used forthe treatment and prophylaxis of allodynia and more specificallymechanical or thermal allodynia.

In another preferred embodiment compounds of the invention are used forthe treatment and prophylaxis of hyperalgesia.

In yet another preferred embodiment compounds of the invention are usedfor the treatment and prophylaxis of neuropathic pain and morespecifically for the treatment and prophylaxis of hyperpathia.

A related aspect of the invention refers to the use of compounds offormula (I) for the manufacture of a medicament for the treatment andprophylaxis of disorders and diseases mediated by σ receptors, asexplained before.

In particular the invention refers to the use of compounds of formula(I) for the manufacture of a medicament for the treatment andprophylaxis of diarrhoea, lipoprotein disorders, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, obesity, migraine, pain,arthritis, hypertension, arrhythmia, ulcer, glaucoma, learning, memoryand attention deficits, cognition disorders, neurodegenerative diseases,demyelinating diseases, addiction to drugs and chemical substancesincluding cocaine, amphetamine, ethanol and nicotine; tardivediskinesia, ischemic stroke, epilepsy, stroke, stress, cancer, psychoticconditions, in particular depression, anxiety or schizophrenia;inflammation or autoimmune diseases.

Especially, the invention refers to the use of compounds of formula (I)for the manufacture of a medicament for the treatment and prophylaxis ofpain, especially neuropathic pain, inflammatory pain or other painconditions involving allodynia and/or hyperalgesia, and more preferablymedium to severe pain, visceral pain, chronic pain, cancer pain,migraine, inflammatory pain, acute pain or neuropathic pain, allodyniaor hyperalgesia, also preferably including mechanical allodynia orthermal hyperalgesia.

A further related aspect of the present invention relates to a method oftreating or preventing disorders and diseases mediated by σ receptorswhich method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound as abovedefined or a pharmaceutical composition thereof. Preferably thedisorders and diseases mediated by σ receptors are chosen among the painsyndromes, and especially medium to severe pain, visceral pain, chronicpain, chronic pain, cancer pain, migraine, inflammatory pain, acute painor neuropathic pain, allodynia or hyperalgesia, whereas this could alsoinclude mechanical allodynia or thermal hyperalgesia.

Another aspect of the invention is a pharmaceutical composition whichcomprises at least a compound of general formula (I) or apharmaceutically acceptable salt, prodrug, isomer or solvate thereof,and at least a pharmaceutically acceptable carrier, additive, adjuvantor vehicle.

The pharmaceutical composition of the invention can be formulated as amedicament in different pharmaceutical forms comprising at least acompound binding to the sigma receptor and optionally at least onefurther active substance and/or optionally at least one auxiliarysubstance.

The auxiliary substances or additives can be selected among carriers,excipients, support materials, lubricants, fillers, solvents, diluents,colorants, flavour conditioners such as sugars, antioxidants and/oragglutinants.

In the case of suppositories, this may imply waxes or fatty acid estersor preservatives, emulsifiers and/or carriers for parenteralapplication. The selection of these auxiliary materials and/or additivesand the amounts to be used will depend on the form of application of thepharmaceutical composition.

The pharmaceutical composition in accordance with the invention can beadapted to any form of administration, be it orally or parenterally, forexample pulmonarily, nasally, rectally and/or intravenously.

Preferably, the composition is suitable for oral or parenteraladministration, more preferably for oral, intravenous, intraperitoneal,intramuscular, subcutaneous, intrathekal, rectal, transdermal,transmucosal or nasal administration.

The composition of the invention can be formulated for oraladministration in any form preferably selected from the group consistingof tablets, dragées, capsules, pills, chewing gums, powders, drops,gels, juices, syrups, solutions and suspensions.

The composition of the present invention for oral administration mayalso be in the form of multiparticulates, preferably microparticles,microtablets, pellets or granules, optionally compressed into a tablet,filled into a capsule or suspended in a suitable liquid. Suitableliquids are known to those skilled in the art.

Suitable preparations for parenteral applications are solutions,suspensions, reconstitutable dry preparations or sprays.

The compounds of the invention can be formulated as deposits indissolved form or in patches, for percutaneous application.

Skin applications include ointments, gels, creams, lotions, suspensionsor emulsions.

The preferred form of rectal application is by means of suppositories.

The respective medicament may—depending on its route ofadministration—also contain one or more auxiliary substances known tothose skilled in the art. The medicament according to the presentinvention may be produced according to standard procedures known tothose skilled in the art.

The daily dosage for humans and animals may vary depending on factorsthat have their basis in the respective species or other factors, suchas age, sex, weight or degree of illness and so forth. The daily dosagefor humans may preferably be in the range from 1 to 2000, preferably 1to 1500, more preferably 1 to 1000 milligrams of active substance to beadministered during one or several intakes per day.

The following examples are merely illustrative of certain embodiments ofthe invention and cannot be considered as restricting it in any way.

EXAMPLES Preparation A8-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepineA.1. 3-((1H-Imidazol-4-yl)methylamino)propan-1-ol

1H-Imidazole-4-carbaldehyde (2.96 g, 30.8 mmol) was suspended inabsolute ethanol (50 mL) and 3-aminopropan-1-ol (2.36 mL, 30.8 mmol) wasadded. After 2.5 h of stirring at room temperature the imine formationwas complete as judged by proton NMR. After cooling the mixture to 0°C., sodium triacetoxyborohydride (32.6 g, 154 mmol) was addedportionwise followed by extra ethanol (75 mL). The cooling bath wasremoved and the mixture was stirred overnight. LC/MS showed completereduction and the mixture corresponding to the title compound wasemployed directly in the next step.

LC/MS m/z 156 [M+H]⁺.

A.2. 3-(((1H-Imidazol-4-yl)methyl)(cyclohexylmethyl)amino)-propan-1-01

The crude mixture of 3-((1H-imidazol-4-yl)methylamino)propan-1-ol (˜30.8mmol in 125 mL absolute ethanol) was treated withcyclohexanecarbaldehyde (10.40 g, 93 mmol) and stirred for 2.5 h at roomtemperature. Then the mixture was cooled in an ice-bath and sodiumtriacetoxyborohydride (32.6 g, 154 mmol) was added followed byadditional 30 mL of absolute ethanol. The mixture was allowed to warm toroom temperature and then stirred for 1 h. After quenching with waterthe mixture was rendered neutral with 1M aqueous sodium hydroxide.Ethanol was removed on a rotavapor and the residue was extracted withethyl acetate to remove some impurities. The aqueous layer was furtherbasified with to pH ˜14 and extracted three times with ethyl acetate.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. The crude title compound (5.73 g),obtained as nearly colourless oil, showed sufficient purity to beemployed in the next step.

¹H NMR (CDCl₃) δ 7.62-7.55 (m, 1H), 6.93 (s, 1H), 3.83-3.74 (m, 2H),3.59 (s, 2H), 2.73-2.63 (m, 2H), 2.27 (d, J=7.1 Hz, 2H), 1.80-1.46 (m,9H), 1.30-1.05 (m, 4H), 0.94-0.75 (m, 2H).

LC/MS m/z 252 [M+H]⁺.

A.3.N-((1H-Imidazol-4-yl)methyl)-3-chloro-N-(cyclohexylmethyl)-propan-1-aminedihydrochloride

3-(((1H-Imidazol-4-yl)methyl)(cyclohexylmethyl)amino)propan-1-ol (5.73g, 19.83 mmol) was dissolved in dichloromethane (110 mL) under anitrogen atmosphere. After cooling down to ˜0° C. thionyl chloride (5.79mL, 79 mmol) was added dropwise, then the mixture was stirred overnightat room temperature. Next, additional 4 equivalents of SOCl₂ were addedin two portions driving the reaction to completion after overnightstirring. After stripping with dichloromethane the crude title compound(˜6.2 g) was obtained as yellow foam.

LC/MS m/z 270 & 272 [M+H]⁺.

A.4.8-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine

N-((1H-Imidazol-4-yl)methyl)-3-chloro-N-(cyclohexylmethyl)propan-1-aminedihydrochloride (19.8 mmol, 6.80 g) was suspended in acetonitrile (dry,130 mL). The suspension was placed under a nitrogen atmosphere andtriethylamine (10 mL, 71.7 mmol) was added. The reaction mixture washeated at reflux for ˜5 h and then stirred at room temperatureovernight. After concentration the product was purified by flash columnchromatography to give the title compound (1.73 g).

¹H NMR (CDCl₃) δ 7.37 (d, J=1.2 Hz, 1H), 6.85 (s, 1H), 4.07-4.02 (m,2H), 3.80 (s, 2H), 3.08 (distorted dd, J=6.5, 3.8 Hz, 2H), 2.11 (d,J=7.1 Hz, 2H), 1.85-1.60 (m, 7H), 1.47-1.35 (m, 1H), 1.30-1.07 (m, 3H),0.89-0.75 (m, 2H).

LC/MS m/z 234 [M+H]⁺.

Preparation B 7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine B.1.2-(((1H-Imidazol-4-yl)methyl)(benzyl)amino)ethanol

A 1 litre flask was charged with 1H-imidazole-4-carbaldehyde (14 g, 146mmol) and absolute ethanol (240 mL). Then 2-(benzylamino)ethanol (20.8mL, 146 mmol) was added and the white suspension turned slowly into ayellow solution after 3 h The mixture was then cooled in an ice-bath andsodium triacetoxyborohydride (93 g, 437 mmol) was added portionwise. Themixture was then stirred overnight at room temperature. Water was addedand the mixture was partially concentrated. After neutralising to pH ˜7with 1M aqueous NaOH, the aqueous phase was rinsed twice with ethylacetate, then it was basified further to pH 14. The aqueous layer wasthen extracted with thrice with ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered and evaporated todryness to give the title compound (26.9 g), which was directly used inthe next step.

¹H NMR (CDCl₃) δ 7.52 (s, 1H), 7.37-7.18 (m, 6H), 6.87 (s, 1H), 3.69 (s,2H), 3.68-3.58 (m, 5H), 2.70 (t, J=5.1 Hz, 2H).

LC/MS: m/z 232 [M+H]⁺.

B.2 N-((1H-Imidazol-4-yl)methyl)-N-benzyl-2-chloroethanaminedihydrochloride

2-(((1H-Imidazol-4-yl)methyl)(benzyl)amino)ethanol (˜112 mmol) wasdissolved in dichloromethane (600 mL) and the solution was placed undera nitrogen atmosphere. After cooling in ice-bath, thionyl chloride (33mL, 452 mmol) was added dropwise. Upon completing the addition themixture was allowed to stir at room temperature for 3 days. Then it wasconcentrated and coevaporated with dichloromethane to give the titlecompound as a dark yellow solid (47 g).

¹H NMR (DMSO) δ 9.22 (s, 1H), 7.91 (br s, 1H), 7.64 (br s, 2H), 7.43 (brs, 3H), 4.67-4.20 (m, 5H), 3.99 (br s, 2H), 3.22 (br s, 2H).

LC/MS m/z 250 & 252 [M+H]⁺.

B.3. 7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

N-((1H-Imidazol-4-yl)methyl)-N-benzyl-2-chloroethanamine dihydrochloride(46.2 g, ˜95 mmol) was suspended in anhydrous acetonitrile (900 mL) andthe solution was placed under nitrogen atmosphere. Triethylamine (46.1mL, 331 mmol) was added and the mixture was refluxed overnight. The darkreaction mixture was cooled down, concentrated and then diluted withdichloromethane and saturated aqueous sodium carbonate. Extractionprovided the crude product, that was purified by column chromatographyusing a gradient of methanol in ethyl acetate, to give the titlecompound as an orange solid (12.7 g).

¹H NMR (CDCl₃) δ 7.40 (s, 1H), 7.39-7.27 (m, 5H), 6.74 (s, 1H), 4.04 (t,J=5.4 Hz, 2H), 3.70 (s, 2H), 3.67 (s, 2H), 2.84 (t, J=5.7 Hz, 2H).

LC/MS m/z 214 [M+H]⁺.

Preparation C7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine C.1.5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazine

7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (4.89 g, 22.9 mmol)was dissolved in absolute ethanol (200 mL) and 10% palladium on carbon(4.88 g) was added to the solution. The mixture was placed under 1 barof a hydrogen atmosphere and stirred vigorously overnight. Then it wasfiltered through celite rinsing with ethanol, concentrated andcoevaporated with dichloromethane. The title compound was obtained asoff-white oil (2.52 g).

¹H NMR (CDCl₃) δ 7.42 (s, 1H), 6.77 (s, 1H), 4.07 (s, 2H), 3.99 (t,J=5.6 Hz, 2H), 3.22 (t, J=5.6 Hz, 2H), 1.76 (br s, 1H).

LC/MS m/z 124 [M+H]⁺.

C.2. 7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazine (1.0 g, 7.71 mmol) wasdissolved in absolute ethanol (50 mL) and the solution was placed undera nitrogen atmosphere. Cyclohexanecarbaldehyde (1.86 mL, 15.4 mmol) wasadded and the reaction mixture was stirred 2 h at room temperature. Thenit was cooled in an ice-bath and sodium triacetoxyhydroborate (6.54 g,30.9 mmol) was added portionwise. Stirring was continued at roomtemperature overnight, after which the reaction mixture was concentratedand partitioned between dichloromethane and water. After separation ofthe layers, the aqueous layer was basified to pH ˜14. and it wasextracted with dichloromethane three times. The combined extracts weredried over sodium sulfate, filtered and concentrated. Flashchromatography (gradient of methanol in dichloromethane) gave the titlecompound as a light yellow solid (1.82 g).

¹H NMR (CDCl₃) δ 7.51 (s, 1H), 6.78 (s, 1H), 4.05 (t, J=5.5 Hz, 2H),3.61 (s, 2H), 2.79 (t, J=5.5 Hz, 2H), 2.32 (d, J=7.2 Hz, 2H), 1.85-1.62(m, 5H), 1.60-1.46 (m, 1H), 1.32-1.10 (m, 3H), 0.98-0.82 (m, 2H).

LC/MS m/z 220 [M+H]⁺.

Example 11-(8-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-yl)-3-ethylurea1.13-Azido-8-(cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine

8-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine,described in preparation A, (1.883 g, 7.1 mmol) was dissolved in drytetrahydrofuran (35 mL) and cooled to −78° C. under an atmosphere ofnitrogen. N-Butyllithium (4.88 mL of 1.6M solution in hexanes, 7.81mmol) was then added dropwise. After 30 minutes 4-methylbenzenesulfonylazide (9.57 g, 7.28 mmol, 15 wt % solution in toluene) was addeddropwise and the mixture, was stirred for 1 h at −78° C. Next, themixture was quenched with water and allowed to stir overnight at roomtemperature. The mixture was extracted with ethyl acetate from dilutedaqueous sodium carbonate, the organic extracts washed with brine, driedover sodium sulphate, filtered and evaporated to dryness. The crude waspurified on silica (gradient of methanol in dichloromethane) to give thetitle compound as an orange oil (0.92 g).

LC/MS m/z 275 [M+H]⁺.

1.2.8-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine

3-Azido-8-(cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine(1.078 g, 3.3 mmol) was dissolved in a mixture of ethanol (25 mL) andethyl acetate (25 mL). The solution was subjected to hydrogenolysisusing 10% palladium on carbon under 1 bar of hydrogen at 60° C. for 2 h.Then the mixture was filtered through celite and evaporated to dryness.Flash column on silica gel (gradient of 7N methanolic ammonia indichloromethane) gave the title compound as a yellow solid (0.69 g).

LC/MS mass 249 [M+H]⁺.

1.31-(8-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-yl)-3-ethylurea

8-(Cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine(0.279 g, 1.0 mmol) was dissolved in dichloromethane (dry, 10 mL) underan atmosphere of nitrogen. The solution was treated with the solution ofisocyanatoethane (0.095 mL, 1.200 mmol) in dichloromethane (dry, 1 mL)and stirred for 2 days at room temperature controlling the progress ofthe reaction. The mixture was then quenched with methanol. Purificationby first straight phase and then reversed phase column chromatographyprovided the title compound as a white solid (86 mg).

¹H NMR (CDCl₃) δ: 6.48 (s, 1H), 4.18-3.88 (m, 2H), 3.70 (s, 2H),3.38-3.22 (m, 2H), 3.04 (dd, J=6.9, 3.5 Hz, 2H), 2.14 (d, J=7.0 Hz, 2H),1.87-1.56 (m, 7H), 1.48-1.30 (m, 1H), 1.30-1.08 (m, 3H), 1.19 (t, J=7.2Hz, 3H), 0.82 (qd, J=13.7, 12.7, 3.5 Hz, 2H).

LC/MS m/z 320 [M+H]⁺.

Example 21-(7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-ethylurea2.13-Azido-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (1.120 g,4.7 mmol), described in preparation C, was dissolved in drytetrahydrofuran (20 mL) under an atmosphere of nitrogen and the solutionwas cooled to −78° C. n-Butyllithium in hexanes (3.08 mL, 4.94 mmol) wasadded dropwise followed after 1 h by 4-dodecylbenzenesulfonyl azide(mixture of isomers, 1.886 mL, 5.64 mmol) The cooling bath was removedand the mixture was allowed to warm up to room temperature whilestirring for 2 h. Then the mixture was quenched with water, aqueoussodium bicarbonate was added and the mixture was extracted with ethylacetate. The extracts were washed with water, then brine and dried oversodium sulfate. The crude product was purified by column chromatographyusing first a gradient of ethyl acetate in heptane, then of methanol inethyl acetate. The title compound was obtained as a brown oil (0.55 g).

¹H NMR (CDCl₃) δ 6.60 (s, 1H), 3.98 (dd, J=11.0, 3.3 Hz, 2H), 3.72 (t,J=5.6 Hz, 2H), 3.57 (s, 2H), 3.39 (td, J=11.9, 1.9 Hz, 2H), 2.80-2.73(m, 2H), 2.37 (d, J=7.2 Hz, 2H), 1.84-1.71 (m, 1H), 1.71-1.64 (m, 2H),1.28 (qd, J=12.0, 4.4 Hz, 2H).

LC/MS m/z 262 [M+H]⁺.

2.2 7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

3-Azido-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine(1.144 g, 4.35 mmol) was dissolved in ethyl acetate (25 mL) and ethanol(25 mL), 10% palladium on carbon (0.231 g, 0.218 mmol) was added and themixture was subjected to hydrogenolysis under 1 bar of hydrogen for 3 hat room temperature. The mixture was then filtered through celite andthe brown filtrate concentrated to dryness and the residue strippedtwice with dichloromethane. The crude title compound (0.95 g) wasemployed as such in the next step.

¹H NMR (CDCl₃) δ 6.34 (s, 1H), 3.81 (br s, 2H), 3.69 (t, J=5.8 Hz, 2H),3.52 (s, 2H), 2.77 (t, J=5.6 Hz, 2H), 2.29 (d, J=7.2 Hz, 2H), 2.01 (brs, 1H), 1.84-1.62 (m, 4H), 1.59-1.44 (m, 1H), 1.32-1.10 (m, 3H),0.97-0.80 (m, 2H).

LC/MS m/z 235 [M+H]⁺.

2.31-(7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-ethylurea

7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine(0.117 g, 0.50 mmol) was suspended in anhydrous dichloromethane (2 mL)under a nitrogen atmosphere and treated with isocyanatoethane (0.047 mL,0.60 mmol). The stirring was continued overnight at room temperature.The mixture was then quenched with a few drops of methanol and purifiedby flash chromatography (gradient methanol in dichloromethane) to givethe title compound as a pale yellow solid (48 mg).

¹H NMR (CDCl₃) δ: 9.13-8.21 (m, 2H), 6.42 (s, 1H), 3.84 (t, J=5.7 Hz,2H), 3.52 (s, 2H), 3.33 (qd, J=7.2, 5.4 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H),2.29 (d, J=7.1 Hz, 2H), 1.84-1.61 (m, 5H), 1.59-1.43 (m, 1H), 1.33-1.08(m, 3H), 1.19 (t, J=7.2 Hz, 3H), 0.89 (qd, J=11.8, 3.0 Hz, 2H).

LC/MS m/z 306 [M+H]⁺.

Example 31-(7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-propylurea

7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine (30mg, 0.128 mmol), described in example 2.2, was dissolved in drydichloromethane (1 mL) under a nitrogen atmosphere. n-Propyl isocyanate(73 μl, 0.768 mmol) was added and the orange solution was stirred atroom temperature for 1 h giving almost a complete conversion towards amixture of mono- and di-urea derivatives. The reaction mixture wasconcentrated and then the residue was redissolved in methanol (1 mL). Anexcess of solid potassium carbonate was added giving after 2 h ofreaction almost exclusively the desired mono-urea product. The reactionmixture was concentrated and the residue diluted with water andextracted with dichloromethane. The crude product obtained after dryingover sodium sulfate, filtration and solvent evaporation was purifiedusing flash chromatography on silica using a gradient of ethyl acetatein dichloromethane, then of methanolic ammonia in ethyl acetate. A purebatch of the title compound was obtained (23 mg).

¹H NMR (CDCl₃) δ: 9.53-8.55 (m, 1H), 7.81-7.34 (m, 1H), 6.41 (s, 1H),3.76 (t, J=5.6 Hz, 2H), 3.52 (s, 2H), 3.26 (q, J=6.7 Hz, 2H), 2.78 (t,J=5.7 Hz, 2H), 2.29 (d, J=7.2 Hz, 2H), 1.82-1.45 (m, 8H), 1.31-1.08 (m,3H), 0.95 (t, J=7.4 Hz, 3H), 1.00-0.80 (m, 2H).

LC/MS m/z 320 [M+H]⁺.

Example 4 was prepared following the same method as in example 3, usingthe appropriate isocyanate.

EX Structure Name NMR 4

1-tert-butyl-3-(7- (cyclohexylmethyl)- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3-yl)urea ¹H NMR (CDCl₃) δ: 8.82 (s, 1H), 7.30- 7.11 (m, 1H),6.43 (s, 1H), 3.89-3.66 (m, 2H), 3.52 (s, 2H), 2.77 (t, J = 5.7 Hz, 2H),2.28 (d, J = 7.2 Hz, 2H), 1.87- 1.62 (m, 5H), 1.61-1.45 (m,1H), 1.40 (s,9H), 1.30-1.11 (m, 3H), 1.02-0.78 (m, 2H).

Example 57-(Cyclohexylmethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine(117 mg, 0.50 mmol) described in example 2.2, bromobenzene (63 μl, 0.60mmol),dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(16 mg, 6 mol %), Pd₂(dba)₃ (6.9 mg, 1.5 mol %) and sodium tert-butoxide(58 mg, 0.60 mmol) were combined in a 8 mL vial, suspended in1,4-dioxane (extra dry, 1 mL), and argon was passed through the mixturefor a while. The vial was capped and stirred at 100° C. for 3 h. Themixture was then cooled down, diluted with dichloromethane and filteredthrough Celite. The concentrated filtrate was purified on a silica gelcolumn (gradient of 10% methanol/ethyl acetate mixture indichloromethane to give the title compound as an off-white solid (94mg).

¹H NMR (CDCl₃) δ: 7.22 (t, J=7.9 Hz, 2H), 6.91-6.82 (m, 3H), 6.62 (s,1H), 5.77 (s, 1H), 3.74 (t, J=5.6 Hz, 2H), 3.59 (s, 2H), 2.75 (t, J=5.6Hz, 2H), 2.31 (d, J=7.2 Hz, 2H), 1.86-1.61 (m, 5H), 1.59-1.45 (m, 1H),1.31-1.11 (m, 3H), 0.90 (qd, J=12.0, 3.2 Hz, 2H).

LC/MS m/z 311 [M+H]⁺.

Examples 6-22 were prepared following the same method as in example 5,using the appropriate arylbromide.

EX Structure Name NMR  6

7- (cyclohexylmethyl)- N-(3,5- difluorophenyl)- 5,6,7,8-tetrahydroimidazo [1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 6.64 (s,1H), 6.44 (s, 1H), 6.43-6.31 (m, 2H), 6.27 (tt, J = 9.0, 2.3 Hz, 1H),3.75 (t, J = 5.5 Hz, 2H), 3.59 (s, 2H), 2.76 (t, J = 5.5 Hz, 2H), 2.31(d, J = 7.1 Hz, 2H), 1.86-1.63 (m, 5H), 1.61-1.43 (m, 1H), 1.33-1.09 (m,3H), 0.98-0.80 (m, 2H).  7

7- (cyclohexylmethyl)- N-(3- methoxyphenyl)- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 7.12 (t, J = 8.1 Hz, 1H), 6.62(s, 1H), 6.48-6.39 (m, 3H), 5.79 (s, 1H), 3.76 (s, 3H), 3.74 (t, J = 5.8Hz, 2H), 3.58 (s, 2H), 2.74 (t, J = 5.6 Hz, 2H), 2.30 (d, J = 7.2 Hz,2H), 1.86-1.63 (m, 5H), 1.60- 1.44 (m, 1H), 1.32-1.09 (m, 3H), 0.89 (qd,J = 12.2, 3.2 Hz, 2H).  8

7- (cyclohexylmethyl)- N-(4- fluorophenyl)- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 6.98-6.85 (m, 4H), 6.58 (s,1H), 5.68 (s, 1H), 3.72 (t, J = 5.6 Hz, 2H), 3.58 (s, 2H), 2.75 (t, J =5.6 Hz, 2H), 2.31 (d, J = 7.2 Hz, 2H), 1.88-1.62 (m, 5H), 1.61-1.43 (m,1H), 1.32-1.10 (m, 3H), 0.90 (qd, J = 11.9, 3.1 Hz, 2H).  9

7-benzyl-N-(3- chloro-2- fluorophenyl)- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 7.42-7.24 (m, 6H), 6.94 (td, J= 8.1, 1.5 Hz, 1H), 6.86 (ddd, J = 8.1, 6.5, 1.6 Hz, 1H), 6.61 (s, 1H),5.93 (s, 1H), 3.80 (t, J = 5.6 Hz, 2H), 3.71 (s, 2H), 3.65 (s, 2H), 2.86(t, J = 5.6 Hz, 2H). 10

7-benzyl-N- phenyl-5,6,7,8- tetrahydroimidazo [1,5-a]pyrazin-3- amine ¹HNMR (CDCl₃) δ: 7.41-7.25 (m, 5H), 7.22 (dd, J = 8.6, 7.2 Hz, 2H),6.94-6.82 (m, 3H), 6.60 (s, 1H), 5.76 (s, 1H), 3.74 (t, J = 5.6 Hz, 2H),3.69 (s, 2H), 3.65 (s, 2H), 2.81 (t, J = 5.6 Hz, 2H). 11

N-(3,5- difluorophenyl)-7- ((tetrahydro-2H- pyran-4- yl)methyl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 6.65 (s,1H), 6.46- 6.34 (m, 2H), 6.30 (tt, J = 9.1, 2.3 Hz, 1H), 6.04 (s, 1H),3.98 (ddd, J = 11.3, 4.7, 1.7 Hz, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.62(s, 2H), 3.40 (td, J = 11.8, 2.0 Hz, 3H), 2.80 (t, J = 5.6 Hz, 2H), 2.39(d, J = 7.1 Hz, 2H), 1.90- 1.74 (m,1H), 1.76-1.64 (m, 2H), 1.37-1.26 (m,2H). 12

N-phenyl-7- ((tetrahydro-2H- pyran-4- yl)methyl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 7.22 (dd, J= 8.8, 7.1 Hz, 2H), 6.93-6.80 (m, 3H), 6.63 (s, 1H), 5.76 (s, 1H), 3.98(ddd, J = 11.6, 4.5, 1.8 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.62 (s,2H), 3.40 (td, J = 11.8, 2.0 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.38 (d,J = 7.2 Hz, 2H), 1.88- 1.74 (m, 1H), 1.74-1.64 (m, 2H), 1.39-1.21 (m,2H). 13

7-benzyl-N-(2- fluorophenyl)- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 7.46-7.26 (m, 6H), 7.09-6.97(m, 2H), 6.87-6.75 (m, 1H), 6.60 (s, 1H), 5.80 (s, 1H), 3.80 (t, J = 5.7Hz, 2H), 3.71 (s, 2H), 3.65 (s, 2H), 2.86 (t, J = 5.6 Hz, 2H). 14

N-(4-((3- (phenylamino)- 5,6- dihydroimidazo [1,5-a]pyrazin- 7(8H)-yl)methyl)phenyl) acetamide ¹H NMR (CDCl₃) δ: 7.47 (d, J = 8.1 Hz, 2H),7.31 (d, J = 8.2 Hz, 2H), 7.23 (dd, J = 8.7, 7.3 Hz, 2H), 7.17 (s, 1H),6.95-6.83 (m, 3H), 6.60 (s, 1H), 5.63 (s, 1H), 3.74 (t, J = 5.6 Hz, 2H),3.65 (s, 2H), 3.63 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.18 (s, 3H). 15

N-(3- methoxyphenyl)- 8-((tetrahydro-2H- pyran-4- yl)methyl)-6,7,8,9-tetrahydro-5H- imidazo[1,5- a][1,4]diazepin-3- amine ¹H NMR (CDCl₃) δ:7.11 (t, J = 8.1 Hz, 1H), 6.75 (s, 1H), 6.43 (dd, J = 8.1, 2.3 Hz, 1H),6.27 (dd, J = 7.9, 2.1 Hz, 1H), 6.23 (t, J = 2.3 Hz, 1H), 5.72 (s, 1H),3.97 (dd, J = 11.4, 3.6 Hz, 2H), 3.94-3.87 (m, 2H), 3.78 (s, 2H), 3.75(s, 3H), 3.39 (td, J = 11.8, 2.0 Hz, 2H), 3.10-3.03 (m, 2H), 2.26 (d, J= 7.0 Hz, 2H), 1.76-1.68 (m, 3H), 1.68-1.60 (m, 2H), 1.33-1.15 (m, 2H).16

N-(4- fluorophenyl)-8- ((tetrahydro-2H- pyran-4- yl)methyl)-6,7,8,9-tetrahydro-5H- imidazo[1,5- a][1,4]diazepin-3- amine ¹H NMR (CDCl₃) δ:6.92 (t, J = 8.7 Hz, 2H), 6.72 (s, 1H), 6.69 (dd, J = 8.9, 4.4 Hz, 2H),5.68 (s, 1H), 3.97 (dd, J = 11.4, 3.5 Hz, 2H), 3.93-3.86 (m, 2H), 3.77(s, 2H), 3.39 (td, J = 11.8, 1.9 Hz, 2H), 3.06 (t, J = 5.0 Hz, 2H), 2.26(d, J = 6.9 Hz, 2H), 1.77-1.68 (m, 3H), 1.68-1.61 (m, 2H), 1.32-1.18 (m,2H). 17

N-(3-chloro-2- fluorophenyl)-8- ((tetrahydro-2H- pyran-4-yl)methyl)-6,7,8,9- tetrahydro-5H- imidazo[1,5- a][1,4]diazepin-3- amine¹H NMR (CDCl₃) δ: 6.96-6.81 (m, 2H), 6.79 (td, J = 7.5, 2.0 Hz, 1H),6.76 (s, 1H), 5.86 (s, 1H), 4.07-3.90 (m, 4H), 3.78 (s, 2H), 3.39 (td, J= 11.8, 2.0 Hz, 2H), 3.12- 3.02 (m, 2H), 2.25 (d, J = 6.9 Hz, 2H), 1.81-1.72 (m, 2H), 1.72-1.67 (m, 1H), 1.64-1.56 (m, 2H), 1.24 (qd, J = 12.8,12.3, 4.4 Hz, 2H). 18

N-(3,5- difluorophenyl)-8- ((tetrahydro-2H- pyran-4- yl)methyl)-6,7,8,9-tetrahydro-5H- imidazo[1,5- a][1,4]diazepin-3- amine ¹H NMR (CDCl₃) δ:6.78 (s, 1H), 6.49 (s, 1H), 6.28 (tt, J = 9.0, 2.2 Hz, 1H), 6.23- 6.11(m, 2H), 3.97 (dd, J = 11.4, 3.5 Hz, 2H), 3.94-3.88 (m, 2H), 3.78 (s,2H), 3.39 (td, J = 11.8, 2.0 Hz, 2H), 3.11-3.01 (m, 2H), 2.25 (d, J =6.9 Hz, 2H), 1.79-1.67 (m, 3H), 1.67-1.60 (m, 2H), 1.34-1.17 (m, 2H). 19

3-(7-benzyl- 5,6,7,8- tetrahydroimidazo [1,5-a]pyrazin-3- ylamino)phenol¹H NMR (DMSO) δ: 9.11 (s, 1H), 8.04 (s, 1H), 7.38-7.32 (m, 4H),7.32-7.23 (m, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.87 (t, J = 2.1 Hz, 1H),6.64 (dd, J = 8.1, 2.0 Hz, 1H), 6.38 (s, 1H), 6.16 (dd, J = 7.9, 2.3 Hz,1H), 3.78 (t, J = 5.6 Hz, 2H), 3.66 (s, 2H), 3.49 (s, 2H), 2.80 (t, J =5.6 Hz, 2H). 20

7-(4- fluorobenzyl)-N- (5-fluoropyridin-2- yl)-5,6,7,8-tetrahydroimidazo [1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 8.04-7.92(m, 1H), 7.39-7.27 (m, 4H), 7.04 (t, J = 8.7 Hz, 2H), 6.49 (s, 1H), 3.83(t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.59 (s, 2H), 2.86 (t, J = 5.7 Hz,2H). 21

7-benzyl-N-(4- fluorophenyl)- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3- amine ¹H NMR (CDCl₃) δ: 7.39-7.32 (m, 4H), 7.36-7.26(m, 2H), 6.96-6.89 (m, 4H), 6.57 (s, 1H), 5.52 (s, 1H), 3.73 (t, J = 5.6Hz, 2H), 3.70 (s, 2H), 3.65 (s, 2H), 2.82 (t, J = 5.6 Hz, 2H). 22

N-(2-bromo-6- chlorophenyl)-8- ((tetrahydro-2H- pyran-4-yl)methyl)-6,7,8,9- tetrahydro-5H- imidazo[1,5- a][1,4]diazepin-3- amine¹H NMR (CDCl₃) δ: 7.44 (dd, J = 8.1, 1.4 Hz, 1H), 7.30 (dd, J = 8.0, 1.4Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 6.66 (s, 1H), 5.77 (s, 1H), 4.24-4.08(m, 2H), 3.96 (dd, J = 11.4, 3.4 Hz, 2H), 3.80 (s, 2H), 3.39 (td, J =11.8, 2.0 Hz, 2H), 3.13 (t, J = 5.2 Hz, 2H), 2.26 (d, J = 6.9 Hz, 2H),1.94-1.77 (m, 2H), 1.74- 1.65 (m, 1H), 1.63-1.55 (m, 2H), 1.23 (qd, J =13.0,12.3, 4.4 Hz, 2H).

Example 23N-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N-phenylpropionamide

7-Benzyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine (61mg, 0.20 mmol), described in example 10, was dissolved indichloromethane (1 mL) and DIPEA (43 μl, 0.240 mmol) was added, followedby propionyl chloride (48 μl, 0.560 mmol added in three portions). Afterovernight stirring at room temperature, the reaction mixture wasquenched with three drops of methanol and it was directly purified onsilica-gel (gradient of 10% methanolic ethyl acetate indichloromethane). Some other impurities and decomposition products wereremoved by preparative LC/MS. The title compound was obtained as a whitesolid (41 mg).

¹H NMR (CDCl₃) δ: 7.41-7.26 (m, 10H), 6.73 (s, 1H), 3.78-3.59 (m, 2H),3.67 (s, 2H), 3.64 (s, 2H), 2.77 (t, J=5.6 Hz, 2H), 2.28 (q, J=7.4 Hz,2H), 1.13 (t, J=7.4 Hz, 3H).

LC/MS m/z 361 [M+H]⁺.

Examples 24-25 were prepared following the same method as in example 23,using the appropriate acyl chloride.

EX Structure Name NMR 24

N-(7-benzyl- 5,6,7,8- tetrahydroimidazo [1,5-a]pyrazin-3-yl)- N-(3-hydroxyphenyl) propionamide ¹H NMR (DMSO) δ: 8.43 (s, 1H), 7.41- 7.30(m, 4H), 7.34-7.23 (m, 2H), 7.24- 7.12 (m, 2H), 6.50 (dt, J = 7.4, 1.8Hz, 1H), 6.40 (s, 1H), 3.81 (t, J = 5.6, Hz 2H), 3.66 (s, 2H), 3.50 (s,2H), 2.81 (t, J = 5.6 Hz, 2H), 2.58 (q, J = 7.5 Hz, 2H), 1.11 (t, J =7.4 Hz, 3H). 25

N-(3- hydroxyphenyl)-N- (7-phenethyl- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3- yl)propionamide ¹H NMR (CDCl₃) δ: 7.35-7.26 (m, 2H),7.26-7.16 (m, 4H), 6.72 (ddd, J = 8.1, 2.2, 0.8 Hz, 1H), 6.67 (t, J =2.2 Hz, 1H), 6.66 (t, J = 0.9 Hz, 1H), 6.60 (ddd, J = 8.1, 2.2, 0.9 Hz,1H), 5.90 (s, 1H), 3.78 (t, J = 5.6 Hz, 2H), 3.74 (s, 2H), 2.93-2.84 (m,4H), 2.84-2.73 (m, 2H), 2.55 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz,3H).

Example 267-Benzyl-N-methyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

7-Benzyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-aminedescribed in example 10 (150 mg, 0.493 mmol) was placed under a nitrogenatmosphere and dissolved in dimethylformamide (1.5 mL). Sodium hydride(22 mg of a 60% dispersion in oil, 0.550 mmol) was added, followed after15 min, by iodomethane (37 μl, 0.591 mmol). After ˜1 h of stirring thereaction mixture was concentrated and it was purified by flash columnchromatography (gradient of methanol in DCM) to give the title compoundas an oil (56 mg).

¹H NMR (CDCl₃) δ: 7.37-7.31 (m, 4H), 7.34-7.25 (m, 1H), 7.23 (dd, J=8.7,7.3 Hz, 2H), 6.87 (tt, J=7.3, 1.1 Hz, 1H), 6.71-6.63 (m, 3H), 3.67 (s,2H), 3.65 (s, 2H), 3.53 (t, J=5.6 Hz, 2H), 3.33 (s, 3H), 2.71 (t, J=5.6Hz, 2H).

LC/MS m/z 319 [M+H]⁺.

Example 27N-Benzyl-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine (20mg, 0.085 mmol), described in example 2.2, was dissolved in dryacetonitrile (1 mL). The solution was placed under nitrogen atmosphereand powdered molecular sieves (˜100 mg, 3 Å) were added. Benzaldehyde(17 μl, 0.168 mmol) was then added and the reaction mixture was stirredfor 4 h at reflux. The mixture was allowed to cool down to roomtemperature and sodium triacetoxyhydroborate (72 mg, 0.340 mmol) wasadded. After stirring overnight, the reaction mixture was quenched withwater and then MeCN was driven off. 1M aqueous NaOH was added to pH ˜14followed by dichloromethane. After extraction, drying and solventevaporation, the crude product was purified by preparative LC/MS to givethe title compound (13.5 mg).

¹H NMR (CDCl₃) δ: 7.40 (d, J=7.5 Hz, 2H), 7.35 (t, J=7.3 Hz, 2H),7.31-7.26 (m, 1H), 6.43 (s, 1H), 4.51 (d, J=5.9 Hz, 2H), 3.62 (t, J=5.6Hz, 2H), 3.58-3.47 (m, 3H), 2.76 (t, J=5.6 Hz, 2H), 2.28 (d, J=7.2 Hz,2H), 1.85-1.62 (m, 5H), 1.55-1.43 (m, 1H), 1.33-1.09 (m, 3H), 0.96-0.75(m, 2H).

LC/MS m/z 325 [M+H]⁺.

Example 283-Benzyl-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinetrifluoroacetate 28.1(7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)(phenyl)methanol

7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (0.142 g,0.50 mmol), described in preparation C, was dissolved in drytetrahydrofuran (2 mL) under an atmosphere of nitrogen. The solution wascooled to −78° C. and was treated with n-butyllithium in hexanes (0.240mL, 0.600 mmol). After stirring for 1 h, benzaldehyde (0.071 mL, 0.700mmol) was added and the cooling bath removed. The mixture was allowed towarm up to room temperature overnight. Then it was quenched with aqueousammonium chloride, diluted with water and extracted with ethyl acetate.The dried and concentrated extracts were purified on silica gel(gradient of 10% methanol/ethyl acetate mixture in dichloromethane) togive the title compound as a nearly colourless glass (138 mg).

¹H NMR (CDCl₃) δ 7.41-7.27 (m, 5H), 6.70 (s, 1H), 5.83 (s, 1H), 3.70(dist. dt, J=11.5, 5.6 Hz, 1H), 3.59 (dist. dt, J=12.0, 5.6 Hz, 2H),3.55 (s, 2H), 2.62 (t, J=5.6 Hz, 2H), 2.24 (d, J=7.2 Hz, 2H), 1.83-1.61(m, 5H), 1.55-1.42 (m, 1H), 1.24-1.10 (m, 3H), 0.85 (dist q, J=˜10.5 Hz,2H).

LC/MS m/z 326 [M+H]⁺.

28.23-Benzyl-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinebis-trifluoroacetate

(7-(Cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)(phenyl)methanol(0.138 g, 0.42 mmol) was treated with a mixture of triethylsilane (1.017mL, 6.30 mmol) and 2,2,2-trifluoroacetic acid (0.468 mL, 6.30 mmol) at100° C. for ˜20 h. The mixture was then concentrated and purified byflash column to give the title compound as a colourless oil (194 mg).

¹H NMR (CDCl₃) δ: 7.38-7.27 (m, 3H), 7.17 (d, J=7.4 Hz, 2H), 7.08 (s,1H), 4.38 (s, 2H), 3.91 (t, J=5.3 Hz, 2H), 3.80 (s, 2H), 3.05-2.92 (m,2H), 2.47 (d, J=6.9 Hz, 2H), 1.83-1.61 (m, 5H), 1.61-1.43 (m, 1H),1.34-1.08 (m, 3H), 1.01-0.75 (m, 2H).

LC/MS m/z 310 [M+H]⁺.

Examples 29-30 were prepared following the same method as in example 28,using the appropriate aldehyde.

EX Structure Name NMR 29

3-(4-fluorobenzyl)-7- ((tetrahydro-2H- pyran-4-yl)methyl)- 5,6,7,8-tetrahydroimidazo [1,5-a]pyrazine hydrochloride ¹H NMR (DMSO) δ: 11.82(s, 1H), 7.56 (s, 1H), 7.40 (dd, J = 8.5, 5.5 Hz, 2H), 7.22 (t, J = 8.8Hz, 2H), 4.45 (s, 2H), 4.51-4.26 (m, 2H), 4.06-3.77 (m, 6H), 3.84 (dd, J= 11.6, 2.9 Hz, 2H), 3.29 (td, J = 11.7, 2.0 Hz, 2H), 2.17-1.97 (m, 1H),1.84-1.64 (m, 2H), 1.34-1.14 (m, 2H). 30

7-(cyclohexylmethyl)- 3-(4-fluorobenzyl)- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine hydrocloride 1H NMR (DMSO) δ: 11.63 (s, 1H), 7.56 (s,1H), 7.41 (dd, J = 8.5, 5.4 Hz, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.84-4.20(m, 6H), 3.78-3.34 (m, 2H), 3.21-2.90 (m, 2H), 1.97- 1.73 (m, 3H),1.76-1.54 (m, 3H), 1.33-1.04 (m, 3H), 1.05-0.82 (m, 2H).

Example 317-Phenethyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine31.1 N-Phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

7-Benzyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine (0.457g, 1.5 mmol) described in example 10 was dissolved in a mixture of ethylacetate (10 mL) and methanol (10 mL). 10% palladium on carbon (600 mg)was added in several portions to the solution stirring first at roomtemperature, then at 50° C. till the completion of reaction as monitoredby TLC. The reaction mixture was then filtered through celite, thefiltration cake rinsed with ethyl acetate and methanol and the filtrateevaporated to dryness. Flash column on silica (gradient of 7 Nmethanolic ammonia in dichloromethane) provided the title compound aswhite foam (159 mg).

¹H NMR (CDCl₃) δ 7.25-7.19 (m, 2H), 6.91-6.85 (m, 3H), 6.64 (s, 1H),5.85 (br s, 1H), 4.05 (d, J=0.8 Hz, 2H), 3.68 (t, J=5.6 Hz, 2H), 3.17(t, J=5.6 Hz, 2H), 1.64 (br s, 1H).

LC/MS m/z 215 [M+H]⁺.

31.27-Phenethyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

N-Phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine (0.053 g, 0.24mmol) was dissolved in absolute ethanol (2 mL) and 2-phenylacetaldehyde(0.037 mL, 0.288 mmol) was added and the mixture was stirred for 1 h.Then, sodium triacetoxyhydroborate (0.153 g, 0.720 mmol) was added andstirring was continued for 1 h more. The mixture was then diluted withDCM, filtered through celite and concentrated to dryness. Flashchromatography on silica (gradient of methanol in dichloromethane)provided the title compound as a yellow glass (58 mg).

¹H NMR (CDCl₃) δ: 7.36-7.26 (m, 2H), 7.27-7.18 (m, 5H), 6.93-6.84 (m,3H), 6.65 (s, 1H), 5.69 (s, 1H), 3.77 (t, J=5.6 Hz, 2H), 3.74 (s, 2H),2.93-2.83 (m, 4H), 2.85-2.75 (m, 2H).

LC/MS m/z 319 [M+H]⁺.

Examples 32-40 were prepared following the same method as in example 31,using the appropriate aldehyde or ketone.

EX Structure Name NMR 32

N-phenyl-7- (tetrahydro-2H-pyran- 4-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 7.22 (t, J = 7.9 Hz, 2H), 6.95-6.82(m, 3H), 6.65 (s, 1H), 5.77 (s, 1H), 4.06 (dd, J = 11.2, 3.9 Hz, 2H),3.79 (s, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.41 (td, J = 11.9, 2.0 Hz, 2H),2.91 (t, J = 5.6 Hz, 2H), 2.65 (tt, J = 11.3, 3.9 Hz, 1H), 1.92-1.76 (m,2H), 1.64 (qd, J = 12.1, 4.4 Hz, 2H). 33

N-phenyl-7-(pyridin- 4-ylmethyl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 8.58 (d, J = 6.0 Hz, 2H), 7.32 (d, J= 5.9 Hz, 2H), 7.26- 7.20 (m, 2H), 6.94-6.84 (m, 3H), 6.62 (s, 1H), 5.66(s, 1H), 3.77 (t, J = 5.6 Hz, 2H), 3.71 (s, 2H), 3.67 (s, 2H), 2.83 (t,J = 5.6 Hz, 2H). 34

3-(7-phenethyl- 5,6,7,8- tetrahydroimidazo[1,5- a]pyrazin-3-ylamino)phenol ¹H NMR (DMSO) δ: 9.11 (s, 1H), 8.04 (s, 1H), 7.34-7.21(m, 4H), 7.18 (td, J = 6.6, 2.7 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.87(t, J = 2.3 Hz, 1H), 6.64 (dd, J = 7.9, 2.1 Hz, 1H), 6.41 (s, 1H), 6.16(dd, J = 7.9, 2.2 Hz, 1H), 3.76 (t, J = 5.6 Hz, 2H), 3.60 (s, 2H),2.89-2.76 (m, 4H), 2.69 (dd, J = 9.2, 6.2 Hz, 2H). 35

7-(2,4- difluorobenzyl)-N-(4- fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 7.39 (td, J =8.4, 6.5 Hz, 1H), 6.98-6.78 (m, 6H), 6.59 (s, 1H), 5.61 (s, 1H), 3.74(t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.66 (s, 2H), 2.85 (t, J = 5.6 Hz,2H). 36

7-((4,4- difluorocyclohexyl) methyl)-N-(4- fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 6.99-6.86 (m,4H), 6.60 (s, 1H), 5.61 (s, 1H), 3.73 (t, J = 5.6 Hz, 2H), 3.61 (s, 2H),2.78 (t, J = 5.6 Hz, 2H), 2.38 (d, J = 7.3 Hz, 2H), 2.20-2.01 (m, 2H),1.96-1.84 (m, 2H), 1.82-1.60 (m, 3H), 1.35-1.17 (m, 2H). 37

N-(4-fluorophenyl)-7- ((5-fluoropyridin-2- yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 8.44 (d, J =2.8 Hz, 1H), 7.46 (dd, J = 8.6, 4.6 Hz, 1H), 7.41 (td, J = 8.3, 2.8 Hz,1H), 6.98- 6.86 (m, 4H), 6.58 (s, 1H), 5.62 (s, 1H), 3.84 (s, 2H), 3.76(t, J = 5.6 Hz, 2H), 3.70 (s, 2H), 2.89 (t, J = 5.6 Hz, 2H). 38

N-(4-fluorophenyl)-7- ((6-fluoropyridin-3- yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 8.17 (d, J =2.4 Hz, 1H), 7.84 (td, J = 8.1, 2.5 Hz, 1H), 6.99-6.87 (m, 5H), 6.59 (s,1H), 5.67 (s, 1H), 3.73 (t, J = 5.6 Hz, 2H), 3.69 (s, 2H), 3.64 (s, 2H),2.83 (t, J = 5.6 Hz, 2H). 39

N-(4-fluorophenyl)-7- ((6-methoxypyridin-3- yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 8.08 (d, J =2.4 Hz, 1H), 7.61 (dd, J = 8.5, 2.4 Hz, 1H),6.98- 6.86 (m, 4H), 6.75 (d,J = 8.5 Hz, 1H), 6.58 (s, 1H), 5.60 (s, 1H), 3.94 (s, 3H), 3.71 (t, J =5.6 Hz, 2H), 3.63 (s, 2H), 3.61 (s, 2H), 2.81 (t, J = 5.6 Hz, 2H). 40

7-cyclohexyl-N-(4- fluorophenyl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3-amine ¹H NMR (CDCl₃) δ: 6.97-6.84 (m, 4H), 6.59 (s, 1H),5.65 (s, 1H), 3.78 (s, 2H), 3.71 (t, J = 5.5 Hz, 2H), 2.91 (t, J = 5.6Hz, 2H), 2.53-2.40 (m, 1H), 1.98-1.77 (m, 4H), 1.34- 1.20 (m, 5H),1.20-1.06 (m, 1H).

Example 417-(3-Methoxyphenethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine

N-Phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine dihydrochloride(150 mg, 0.52 mmol, prepared from example 31.1 using HCl in ethanol) wassuspended in absolute ethanol (10 mL) under a nitrogen atmosphere.Triethylamine (146 μl, 1.04 mmol) was added followed by2-(3-methoxyphenyl)acetaldehyde (1.40 mmol) and a drop of AcOH. Themixture was stirred for 2 h at room temperature, then sodiumtriacetoxyborohydride (332 mg, 1.567 mmol) was added and the suspensionwas stirred at room temperature overnight. After quenching with water,ethanol was driven off and the residue was diluted with dichloromethaneand aqueous sodium bicarbonate. The crude product obtained afterextraction, drying, filtration and solvent evaporation was purified byflash chromatography (gradient of methanol in dichloromethane) andpreparative LC/MS to give the title compound as a white solid (81 mg).

LC/MS m/z 349 [M+H]⁺.

Examples 42-44 were prepared following the same method as in example 47,using the appropriate aldehyde.

EX Structure Name NMR 42

7-(4- methoxyphenethyl)- N-phenyl-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin- 3-amine 43

7-(3-(3- methoxyphenyl) propyl)-N-phenyl- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin- 3-amine 44

7-(3-(4- methoxyphenyl) propyl)-N-phenyl- 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin- 3-amine

Example 453-(2-(3-(Phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethyl)phenol

7-(3-Methoxyphenethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine(0.80 g, 0.23 mmol), described in example 47, was dissolved indichloromethane (10 mL). The solution was cooled to −78° C. and it wastreated with an excess of tribromoborane (0.766 mL, 1.532 mmol). Thereaction mixture as a white suspension was allowed to warm up to roomtemperature. Then the mixture was quenched with water and methanol andextracted with dichloromethane from aqueous sodium bicarbonate. Thecrude product was first purified using flash chormatography on silicagel (gradient of 7N methanolic ammonia in ethyl acetate) and thenpurified further by means of preparative TLC. The title compound wasobtained as a white solid after freeze-drying from acetonitrile (58 mg).

¹H NMR (DMSO) δ: 9.26 (s, 1H), 8.19 (s, 1H), 7.35 (d, J=8.0 Hz, 2H),7.17 (t, J=7.8 Hz, 2H), 7.06 (t, J=7.7 Hz, 1H), 6.76 (t, J=7.3 Hz, 1H),6.66 (d, J=8.0 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.58 (dd, J=7.9, 2.3 Hz,1H), 6.41 (s, 1H), 3.78 (t, J=5.6 Hz, 2H), 3.59 (s, 2H), 2.84 (t, J=5.6Hz, 2H), 2.77-2.69 (m, 2H), 2.69-2.62 (m, 2H).

LC/MS m/z 335 [M+H]⁺, m/z 333 [M−H]⁻.

Examples 46-48 were prepared following the same method as in example 51,starting from the corresponding examples 48 to 50.

EX Structure Name NMR 46

4-(2-(3- (phenylamino)-5,6- dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)ethyl)phenol ¹H NMR (DMSO) δ: 9.16 (s, 1H), 8.18 (s, 1H), 7.34 (d, J= 7.9 Hz, 2H), 7.17 (t, J = 7.8 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.76(t, J = 7.3 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H), 6.41 (s, 1H), 3.77 (t, J= 5.6 Hz, 2H), 3.58 (s, 2H), 2.83 (t, J = 5.6 Hz, 2H), 2.74-2.65 (m,2H), 2.65-2.58 (m, 2H). 47

3-(3-(3- (phenylamino)-5,6- dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)propyl)phenol ¹H NMR (DMSO) δ: 9.24 (s, 1H), 8.18 (s, 1H), 7.34 (d, J= 7.8 Hz, 2H), 7.17 (dd, J = 8.5, 7.2 Hz, 2H), 7.05 (t, J = 7.7 Hz, 1H),6.75 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 2.1 Hz,1H), 6.56 (dd, J = 7.8, 2.0 Hz, 1H), 6.41 (s, 1H), 3.78 (t, J = 5.6 Hz,2H), 3.51 (s, 2H), 2.76 (t, J = 5.6 Hz, 2H), 2.53 (t, J = 7.7 Hz, 2H),2.45 (t, J = 7.3 Hz, 2H), 1.76 (p, J = 7.5 Hz, 2H). 48

4-(3-(3- (phenylamino)-5,6- dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)propyl)phenol ¹H NMR (DMSO) δ: 9.13 (s, 1H), 8.18 (s, 1H), 7.34 (d, J= 8.0 Hz, 2H), 7.17 (t, J = 7.9 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.75(t, J = 7.3 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H), 6.40 (s, 1H), 3.77 (t, J= 5.7 Hz, 2H), 3.50 (s, 2H), 2.75 (t, J = 5.6 Hz, 2H), 2.51-2.47 (m,2H), 2.43 (t, J = 7.2 Hz, 2H), 1.73 (p, J = 7.5 Hz, 2H).Biological ActivityPharmacological Study

Brain membrane preparation and binding assays for the σ₁-receptor wereperformed as described (DeHaven-Hudkins, D. L., L. C. Fleissner, and F.Y. Ford-Rice, 1992, Characterization of the binding of[³H](+)pentazocine to σ recognition sites in guinea pig brain, Eur. J.Pharmacol. 227, 371-378) with some modifications. Guinea pig brains werehomogenized in 10 vols. (w/v) of Tris-HCl 50 mM 0.32 M sucrose, pH 7.4,with a Kinematica Polytron PT 3000 at 15000 r.p.m. for 30 s. Thehomogenate was centrifuged at 1000 g for 10 min at 4° C. and thesupernatants collected and centrifuged again at 48000 g for 15 min at 4°C. The pellet was resuspended in 10 volumes of Tris-HCl buffer (50 mM,pH 7.4), incubated at 37° C. for 30 min, and centrifuged at 48000 g for20 min at 4° C. Following this, the pellet was re-suspended in freshTris-HCl buffer (50 mM, pH 7.4) and stored on ice until use.

The radioligand used was [³H]-(+)-pentazocine at 5.0 nM and the finalvolume was 200 μl. The incubation was initiated with the addition of 100μl of membrane at a final tissue concentration of approximately 5 mgtissue net weight/mL and the incubation time was 150 m. at 37° C. Afterincubation, the membranes were collected onto pretreated glass fiberfilterplate (MultiScreen-FC, Millipore), with polyethylenimine 0.1%. Thefilters were washed two times with 200 μl of washing buffer (50 mM TrisCl, pH=7.4) and then 25 μl of Ecoscint H liquid scintillation cocktailwere added. Microplates were allowed to set for several hours and thenquantified by liquid scintillation spectrophotometry (1450 Microbeta,Wallac). Nonspecific binding was determined with 1 μM haloperidol.

Some of the results obtained are shown in table (I).

TABLE (I) EX K_(i) (nM) 1 179 2 106 3 71 5 8.2 6 12 7 13 8 8 9 232 10 5812 258 15 266 16 175 17 14 18 26 19 63 20 67 21 44 24 124 25 358 27 3828 39 30 22 31 101 34 168 35 37 36 21 37 293 38 311 39 373 40 68

The invention claimed is:
 1. A compound of formula (I):

wherein R₁ is selected from the group consisting of —NR₄COR₃, —NHCONHR₃,—(C(R₅₁R₅₂))_(m)—R₆, and —NR₇₁R₇₂; R₂ is selected from the groupconsisting of —(C(R₈₁R₈₂))_(p)—R₉, a substituted or unsubstitutedcycloalkyl group, and a substituted or unsubstituted heterocycloalkylgroup; R₃ is selected from the group consisting of a linear or branched,substituted or unsubstituted C₁₋₁₀alkyl group, a linear or branched,substituted or unsubstituted C₂₋₁₀alkenyl group, a linear or branched,substituted or unsubstituted C₂₋₁₀alkynyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkylalkyl group, a substituted or unsubstituted heterocycloalkylgroup, and a substituted or unsubstituted heterocycloalkylalkyl group;R₄, is selected from the group consisting of a hydrogen atom, a linearor branched, substituted or unsubstituted C₁₋₁₀alkyl group, a linear orbranched, substituted or unsubstituted C₂₋₁₀alkenyl group, a linear orbranched, substituted or unsubstituted C₂₋₁₀alkynyl group, a substitutedor unsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkylalkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted arylalkyl group, a substituted orunsubstituted heterocycloalkyl group, a substituted or unsubstitutedheterocycloalkylalkyl group, a substituted or unsubstituted heteroarylgroup, and a substituted or unsubstituted heteroarylalkyl group; R₅₁,R₅₂, R₈₁ and R₈₂ are selected independently from the group consisting ofa hydrogen atom, a linear or branched, substituted or unsubstitutedC₁₋₃alkyl group, a linear or branched, substituted or unsubstitutedC₂₋₃alkenyl group, and a linear or branched, substituted orunsubstituted C₂₋₃alkynyl group; R₆ is selected from the groupconsisting of a substituted or unsubstituted aryl group, and asubstituted or unsubstituted heteroaryl group; R₇₁ is selected from thegroup consisting of a substituted or unsubstituted cycloalkyl group, asubstituted or unsubstituted cycloalkylalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted arylalkylgroup, a substituted or unsubstituted heterocycloalkyl group, asubstituted or unsubstituted heterocycloalkylalkyl group, a substitutedor unsubstituted heteroaryl group, and a substituted or unsubstitutedheteroarylalkyl group; R₇₂ is selected from the group consisting of ahydrogen atom, a linear or branched, substituted or unsubstitutedC₁₋₃alkyl group, a linear or branched, substituted or unsubstitutedC₂₋₃alkenyl group, and a linear or branched, substituted orunsubstituted C₂₋₃alkynyl group; R₉ is selected from the groupconsisting of a substituted or unsubstituted cycloalkyl group, asubstituted or unsubstituted aryl group, a substituted or unsubstitutedheterocycloalkyl group, and a substituted or unsubstituted heteroarylgroup; n is 1, 2, or 3; m is 1, 2, or 3; p is 1, 2, or 3; wherein theC₁₋₁₀alkyl group, the C₂₋₁₀alkenyl group, the C₂₋₁₀alkynyl group, thecycloalkyl group, the heterocycloalkyl group, the aryl group and theheteroaryl group as defined in formula (I), if substituted, aresubstituted by one or more substituents selected from the groupconsisting of a C₁₋₆ alkyl group, a linear or branched C₁₋₆ alkoxygroup, —F, —Cl, —I, —Br, —CF₃, —CH₂F, —CHF₂, —CN, —OH, —SH, —NH₂, oxo,—(C═O)R′, —SR′, —SOR′, —SO₂R′, —NHR′, —NR′R″ wherein R′ and R″ for eachsubstituent independently represents a linear or branched C₁₋₆-alkylradical; optionally as a stereoisomer, including enantiomers anddiastereomers, a racemate or a mixture of at least two of thestereoisomers, including enantiomers and diastereomers, in any mixingratio, or a pharmaceutically acceptable salt, or solvate thereof.
 2. Thecompound according to claim 1, wherein R₁ represents —NR₇₁R₇₂.
 3. Thecompound according to claim 1, wherein R₁ represents —NR₇₁R₇₂, whereinR₇₁ is a substituted or unsubstituted aryl group and R₇₂ is a hydrogenatom.
 4. The compound according to claim 1, wherein R₁ represents—(C(R₅₁R₅₂))_(m)—R₆.
 5. The compound according to claim 1, wherein R₁represents a group —(C(R₅₁R₅₂))_(m)—R₆ in which R₆ is a substituted orunsubstituted aryl group.
 6. The compound according to claim 1, whereinR₁ is selected from the group consisting of —NR₄COR₃, and —NHCONHR₃. 7.The compound according to claim 1, wherein R₂ is a —(C(R₈₁R₈₂))_(p)—R₉group in which R₈₁ and R₈₂ each represent a hydrogen atom.
 8. Thecompound according to claim 1, wherein, taken together or separately, nis 1 or 2, m is 1, and p is
 1. 9. The compound according to claim 1,which is selected from the group consisting of:1-(8-(cyclohexylmethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-yl)-3-ethylurea,1-(7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-ethylurea,1-(7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-propylurea,1-tert-butyl-3-(7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)urea,7-(cyclohexylmethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-(cyclohexylmethyl)-N-(3,5-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-(cyclohexylmethyl)-N-(3-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-(cyclohexylmethyl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-benzyl-N-(3-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-benzyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-(3,5-difluorophenyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-phenyl-7-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-benzyl-N-(2-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-(4-((3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl)phenyl)acetamide,N-(3-methoxyphenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,N-(4-fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,N-(3-chloro-2-fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,N-(3,5-difluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,3-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-ylamino)phenol,7-(4-fluorobenzyl)-N-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-benzyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-(2-bromo-6-chlorophenyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepin-3-amine,N-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N-phenylpropionamide,N-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-N-(3-hydroxyphenyl)propionamide,N-(3-hydroxyphenyl)-N-(7-phenethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propionamide,7-benzyl-N-methyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-benzyl-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,3-benzyl-7-(cyclohexylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinetrifluoroacetate,3-(4-fluorobenzyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinehydrochloride,7-(cyclohexylmethyl)-3-(4-fluorobenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinehydrochloride,7-phenethyl-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-phenyl-7-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-phenyl-7-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,3-(7-phenethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-ylamino)phenol,7-(2,4-difluorobenzyl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-((4,4-difluorocyclohexyl)methyl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-(4-fluorophenyl)-7-((5-fluoropyridin-2-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-(4-fluorophenyl)-7-((6-fluoropyridin-3-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,N-(4-fluorophenyl)-7-((6-methoxypyridin-3-yl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-cyclohexyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-(3-methoxyphenethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-(4-methoxyphenethyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-(3-(3-methoxyphenyl)propyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,7-(3-(4-methoxyphenyl)propyl)-N-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine,3-(2-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethyl)phenol,4-(2-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethyl)phenol,3-(3-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)propyl)phenol,and4-(3-(3-(phenylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)propyl)phenol.10. A process for the preparation of a compound of formula (I) accordingto claim 1, starting from a compound of formula (II):

wherein n and R₉ are as defined in claim 1, which compound of formula(II) is reacted with an azidating agent, in the presence of an organicbase, in an inert organic solvent, at low temperatures about −78° C., togive a compound of formula (III):

wherein n and R₉ are as defined in claim 1, which compound of formula(III) is subjected to a reduction by hydrogenation under a hydrogenatmosphere with a suitable catalyst in an organic solvent, includingethanol, methanol, ethyl acetate and mixtures of two of them, oralternatively, in the presence of a suitable reducing agent, including ametallic hydride, in an organic solvent, including diethyl ether, togive a compound of formula (IV):

wherein n and R₉ are as defined in claim 1, which compound of formula(IV) may be reacted with an isocyanate of formula R₃—N═C═O, wherein R₃is as defined in claim 1, to give a bisurea of formula (V):

wherein n, R₃ and R₉ are as defined in claim 1, which compound offormula (V) is reacted with a base, including K₂CO₃, in the presence ofan organic polar solvent, including MeOH, to yield a compound of formula(Ia):

a particular case of the compound of formula (I), wherein R₁ representsa —NHCONHR₃ group and n, R₃ and R₉ are as defined in claim 1, or, thecompound of formula (IV) as defined above may be acylated by a compoundof formula R₃COX where X is an halogen atom and R₃ is as defined inclaim 1, in an aprotic solvent in the presence of an organic base toyield compounds of formula (Ib):

a particular case of the compound of formula (I), wherein R₁ representsa —NR₄COR₃ group, wherein R₄ represents a hydrogen atom, and n, R₃ andR₉ are as defined in claim 1, or, the compound of formula (IV) asdefined above may be reacted with a compound of formula R₇₁X wherein Xis an halogen atom, and R₇₁ is selected from the group consisting of asubstituted or unsubstituted aryl group and a substituted orunsubstituted heteroaryl group, in an aprotic inert organic solvent, inthe presence of a palladium catalyst and an organophosphorous ligand anda base to yield a compound of formula (Ic):

a particular case of the compound of formula (I), wherein R₁ represents—NR₇₁R₇₂, wherein R₇₁ is selected from the group consisting of asubstituted or unsubstituted aryl group and a substituted orunsubstituted heteroaryl group, R₇₂ represents a hydrogen atom, and nand R₉ are as defined in claim 1, which compound of formula (Ic) may besubjected to an acylation reaction with a compound of formula R₃COX,wherein X is an halogen atom and R₃ is as defined in claim 1, in anaprotic solvent in the presence of an organic base to yield a compoundof formula (Id):

a particular case of the compound of formula (I), wherein R₁ representsa —NR₄COR₃ group, wherein n, R₃ and R₉ are as defined in claim 1, and R₄is selected from the group consisting of a substituted or unsubstitutedaryl group and a substituted or unsubstituted heteroaryl group, or thecompound of formula (Ic) may be reacted with a compound of formula R₇₂X,wherein X is an halogen atom, and R₇₂ is a linear or branched,substituted or unsubstituted C₁₋₃alkyl group, a linear or branched,substituted or unsubstituted C₂₋₃alkenyl group, or a linear or branched,substituted or unsubstituted C₂₋₃alkynyl group, in an aprotic polarorganic solvent in the presence of a base to yield a compound of formula(Ie):

a particular case of the compound of formula (I), wherein R₁ representsa —NR₇₁R₇₂ group, wherein R₇₁ is selected from the group consisting of asubstituted or unsubstituted aryl group and a substituted orunsubstituted heteroaryl group, R₇₂ represents a linear or branched,substituted or unsubstituted C₁₋₃alkyl group, a linear or branched,substituted or unsubstituted C₂₋₃alkenyl group, a linear or branched,substituted or unsubstituted C₂₋₃alkynyl group, and n and R₉ are asdefined in claim 1, or the compound of formula (Ic), in the case whereR₉ represents a phenyl group, may be debenzylated followinghydrogenation under palladium catalysis in the presence of an organicsolvent to give a compound of formula (VI):

wherein R₇₁ is selected from the group consisting of a substituted orunsubstituted aryl group and a substituted or unsubstituted heteroarylgroup, and n is as defined in claim 1, which compound of formula (VI) isthen subjected to a reductive amination process by reaction withaldehydes or ketones of formula R₂═O, where R₂ is as defined in claim 1,in the presence of a reducing agent in an inert organic solvent to yielda compound of formula (If):

a particular case of the compound of formula (I), wherein R₁ representsa —NR₇₁R₇₂ group, wherein R₇₁ is selected from the group consisting of asubstituted or unsubstituted aryl group and a substituted orunsubstituted heteroaryl group, R₇₂ represents a hydrogen atom, and, nand R₂ are as defined in claim
 1. 11. A process for the preparation of acompound of formula (I) according to claim 1 starting from a compound offormula (IV)

wherein n and R₉ are as defined in claim 1, which compound of formula(IV) is subjected to a reductive amination process by reaction with analdehyde or ketone of formula R₇₁═O, wherein R₇₁ represents a linear orbranched, substituted or unsubstituted C₁₋₁₀ C₁₋₁₀alkyl group, a linearor branched, substituted or unsubstituted C₂₋₁₀alkenyl group, a linearor branched, substituted or unsubstituted C₂₋₁₀alkynyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted cycloalkylalkyl group, a substituted or unsubstitutedarylalkyl group, a substituted or unsubstituted heterocycloalkyl group,a substituted or unsubstituted heterocycloalkylalkyl group, or anunsubstituted heteroarylalkyl group, in the presence of a reducing agentin an inert organic solvent to yield a compound of formula (Ig):

a particular case of the compound of formula (I), wherein R₁ representsa —NR₇₁R₇₂ group, wherein R₇₁ is selected from the group consisting of alinear or branched, substituted or unsubstituted C₁₋₁₀alkyl group, alinear or branched, substituted or unsubstituted C₂₋₁₀alkenyl group, alinear or branched, substituted or unsubstituted C₂₋₁₀alkynyl group, asubstituted or unsubstituted cycloalkyl group, a a substituted orunsubstituted cycloalkylalkyl group, a substituted or unsubstitutedarylalkyl group, a substituted or unsubstituted heterocycloalkyl group,a substituted or unsubstituted heterocycloalkylalkyl group, or anunsubstituted heteroarylalkyl group, R₇₂ represents a hydrogen atom, andn and R₉ are as defined in claim
 1. 12. A process for the preparation ofa compound of formula (I) according to claim 1, starting from a compoundof formula (II):

wherein n and R₉ are as defined in claim 1, which compound of formula(II) is reacted with a compound of formula R₆—(C(R₅₁R₅₂))_((m′))—CHO,wherein R₆, R₅₁, R₅₂ are as defined in claim 1, and m′ is 0, 1 or 2, togive a compound of formula (VII):

wherein R₅₁, R₅₂, R₆, m′ and n are as defined above and R₉ is as definedin claim 1, which compound of formula (VII) is reduced in the presenceof an organosilane, and an acid to yield a compound of formula (Ih):

a particular case of the compound of formula (I), wherein R₁ representsR₆—(C(R₅₁R₅₂))m′-CH₂—, and R₅₁, R₅₂, R₆, R₉, m′ and n are as definedabove.
 13. A method for the treatment of a sigma receptor mediateddisease or condition selected from the group consisting of diarrhea,lipoprotein disorders, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, obesity, migraine, pain, arthritis, hypertension,arrhythmia, ulcer, glaucoma, learning deficits, memory deficits,attention deficits, cognition disorders, demyelinating diseases,addiction to drugs and chemical substances including cocaine,amphetamine, ethanol and nicotine; tardive dyskinesia, epilepsy, stroke,stress, psychotic conditions, depression, anxiety, and schizophrenia ina subject in need thereof, comprising administration of an effectiveamount of the compound according to claim
 1. 14. A method for thetreatment of neuropathic pain, inflammatory pain or other painconditions involving allodynia and/or hyperalgesia in a subject in needthereof, comprising administration of an effective amount of thecompound according to claim
 1. 15. A pharmaceutical compositioncomprising the compound according to claim 1, or a pharmaceuticallyacceptable salt, isomer, or solvate thereof, and at least apharmaceutically acceptable carrier, additive, adjuvant or vehicle.